Ectonucleotidase Inhibitors and Methods of Use Thereof

ABSTRACT

The invention relates to novel heterocyclic compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cancer using the novel heterocyclic compounds of the invention.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Nos. 62/437,915 filed 22 Dec. 2016, 62/437,935 filed22 Dec. 2016 and 62/555,791 filed 8 Sep. 2017, each of which are herebyincorporated by reference in its entirety.

BACKGROUND

CD73, also referred to as 5′-nucleotidase (5′-NT) orecto-5′-nucleotidase (Ecto 5′NTase), is a membrane-bound cell surfaceenzyme whose primary role is to catalyze the conversion of extracellularnucleotides (e.g., AMP) to their corresponding nucleosides (e.g.,adenosine). CD73 is found in most tissues and expressed on lymphocytes,endothelial cells, and epithelial cells. It is also widely expressed inmany tumor cell lines and, notably, is upregulated in cancerous tissues(Antonioli et al., Nat. Rev. Cancer, 13: 842-857, 2013).

In tandem with CD39 (ecto-ATPase), CD73 generates adenosine fromATP/AMP, which is often released from damaged or inflamed cells into theextracellular environment. Extracellular adenosine produced by CD73interacts with G-protein coupled receptors on target cells. An importantdownstream effect of this signaling is increased immunosuppression via anumber of pathways. For example, CD73 is a co-signaling molecule on Tlymphocytes. Under normal circumstances, extracellular adenosine levelspromote a self-limiting immune response that prevents excessiveinflammation and tissue damage. For tumors, an advantage of abnormallyincreased CD73 is that the resulting increased CD73-catalyzed adenosinelevels yield inhibition of anti-tumor immune system responses.

Even though CD73 plays a role in cancer immunosuppression, higherexpression of CD73 is associated with a variety of stages of tumorprogression, including tumor vascularization, invasiveness, andmetastasis, and with shorter breast cancer patient survival time. Someof these observations result from CD73′s enzyme-independent function asan adhesion molecule required for lymphocyte binding to the endothelium.

Overall, CD73 has become an important target for developing new cancertherapies, either as single agents or in combination with other cancertherapies. Indeed, combining CD73 monoclonal antibodies with antibodiesfor other chemotherapy targets enhances response and survival in animalcancer models (Allard et al., Clin. Cancer Res., 19:5626-35, 2013).

Many of the current cancer treatments and chemotherapeutic agents failto successfully treat all patients or all symptoms in treated patients,and many of these therapies are associated with undesirable sideeffects. As certain cancers develop resistance to variouschemotherapeutic agents, alternate cancer therapies are needed. Thus,there is a need for additional compounds and methods for treating cancerand other diseases.

SUMMARY

Disclosed herein are compounds of Formula (I):

or a pharmaceutically acceptable salt and/or prodrug thereof, wherein

X is O, NR⁷ or CR⁷R⁸;

Y is O or S;

Z is NR¹⁹, O or S;

Het is heterocyclyl or heteroaryl;

R^(1a) is selected from H, halo, hydroxy, cyano, azido, amino,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₆acyloxy,—O—C(O)—O—C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, and C₂₋₆alkynyl; and

R^(1b) is selected from H, halo, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,amino-C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl; or

R^(1a) and R^(1b), together with the carbon atom to which they areattached, form a C═CH₂ or C═C(H)C₁₋₆alkyl;

R^(2a) is selected from H, halo, hydroxy, cyano, azido, amino,C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₆acyloxy,—O—C(O)—O—C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, and C₂₋₆alkynyl;

R^(2b) is selected from H, halo, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,amino-C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl; or

R^(2a) and R^(2b), together with the carbon atom to which they areattached, form a C═CH₂ or C═C(H)C₁₋₆alkyl;

R³ is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and—(CH₂)—C(O)OR₉;

R⁴ is selected from heteroaryl, alkyl, —C(O)OR⁹, —C(O)NR¹¹R¹²,—S(O)₂R¹⁰, —P(O)(OR¹¹)(OR¹²), and —P(O)(OR¹¹)(NR¹³R¹⁵);

R⁵ is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl,aralkyl, heteroaralkyl, and —C(O)OR⁹;

R⁶ is selected from —C(O)OR^(S) and —P(O)(OR¹¹)(OR¹²);

each R⁷ and R⁸ is H

R⁹ is independently selected from H, alkyl, acyloxyalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, and heteroaralkyl, and—(CHR¹³)_(m)Z—C(O)—R¹⁴;

each R¹⁰ is independently selected from alkyl, alkenyl, alkynyl, amino,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,aralkyl, heteroaryl, and heteroaralkyl; and each R¹¹ and R¹² isindependently selected from H, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl and —(CHR¹³)_(m)—Z—C(O)—R¹⁴; or

R¹¹ and R¹², together with the atoms to which they are attached, form a5- to 7-membered heterocyclyl; and

each R¹³ is independently H or alkyl;

each R¹⁴ is independently selected from alkyl, aminoalkyl, heterocyclyl,and heterocyclylalkyl;

R¹⁵ is selected from alkyl, aralkyl, —C(R¹⁶)(R¹⁷)—C(O)O—R¹⁸;

each R¹⁶ and R¹⁷ are selected from H, alkyl, amino-alkyl, hydroxy-alkyl,mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl,heterocyclylalkyl, heteroaralkyl, and —(CH₂)C(O)OR⁹;

R¹⁸ is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl,amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl;

R¹⁹ is H or alkyl, preferably H; and

m is 1 or 2;

provided that either R⁴ is tetrazolyl, or R⁵ is aralkyl orheteroaralkyl, or both.

In certain embodiments, the present invention provides a pharmaceuticalcomposition suitable for use in a subject in the treatment or preventionof cancer comprising an effective amount of any of the compoundsdescribed herein (e.g., a compound of the invention, such as a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, and oneor more pharmaceutically acceptable excipients. In certain embodiments,the pharmaceutical preparations may be for use in treating or preventinga condition or disease as described herein.

Disclosed herein are methods of treating diseases and conditions thatbenefit from the inhibition of CD73, comprising administering to asubject in need thereof an effective amount of a compound as disclosedherein (e.g., a compound of Formula (I) or any of the embodimentsthereof disclosed herein). In certain embodiments, the human subject isin need of such treatment. These diseases include, but are not limitedto cancers, such as lung cancer, kidney cancer, skin cancer, breastcancer, and ovarian cancer. Other diseases and conditions that can betreated using the methods described herein include, but are not limitedto, neurological, neurodegenerative and CNS disorders and diseases suchas depression and Parkinson's disease, cerebral and cardiac ischemicdiseases, sleep disorders, fibrosis, immune and inflammatory disorders.

Provided herein are combination therapies of compounds of formula (I)with monoclonal antibodies and other chemotherapeutic agents that canenhance the therapeutic benefit beyond the ability of the adjuvanttherapy alone.

DETAILED DESCRIPTION

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art ofthe present disclosure. The following references provide one of skillwith a general definition of many of the terms used in this disclosure:Singleton et al., Dictionary of Microbiology and Molecular Biology (2nded. 1994); The Cambridge Dictionary of Science and Technology (Walkered., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.),Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionaryof Biology (1991). As used herein, the following terms have the meaningsascribed to them below, unless specified otherwise.

In some embodiments, chemical structures are disclosed with acorresponding chemical name. In case of conflict, the chemical structurecontrols the meaning, rather than the name.

In this disclosure, “comprises,” “comprising,” “containing” and “having”and the like can have the meaning ascribed to them in U.S. Patent lawand can mean “ includes,” “including,” and the like; “consistingessentially of” or “consists essentially” likewise has the meaningascribed in U.S. Patent law and the term is open-ended, allowing for thepresence of more than that which is recited so long as basic or novelcharacteristics of that which is recited is not changed by the presenceof more than that which is recited, but excludes prior art embodiments.

Unless specifically stated or obvious from context, as used herein, theterm “or” is understood to be inclusive. Unless specifically stated orobvious from context, as used herein, the terms “a”, “an”, and “the” areunderstood to be singular or plural.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, preferably from 1 to about 10 unless otherwise defined. Examplesof straight chained and branched alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group isalso referred to as a “lower alkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat the moieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), —CF₃, —CN andthe like. Exemplary substituted alkyls are described below. Cycloalkylscan be further substituted with alkyls, alkenyls, alkoxys, alkylthios,aminoalkyls, carbonyl-substituted alkyls, —CF3, —CN, and the like.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups that contain from x to y carbons in the chain. Forexample, the term “C_(x-y)alkyl” refers to substituted or unsubstitutedsaturated hydrocarbon groups, including straight-chain alkyl andbranched-chain alkyl groups that contain from x to y carbons in thechain, including haloalkyl groups such as trifluoromethyl and2,2,2-tirfluoroethyl, etc. C₀ alkyl indicates a hydrogen where the groupis in a terminal position, a bond if internal. The terms“C_(2-y)alkenyl” and “C_(2-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein each R³⁰ independently represents a hydrogen or hydrocarbylgroup, or two R³⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R³¹ independently represents a hydrogen or a hydrocarbylgroup, or two R³¹ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure. The term “aminoalkyl”, as used herein, refers to an alkylgroup substituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably, the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “carbamate” is art-recognized and refers to a group

wherein R³² and R³³ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R³² and R³³ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond.

The term “carbocycle” includes 5-7 membered monocyclic and 8-12 memberedbicyclic rings. Each ring of a bicyclic carbocycle may be selected fromsaturated, unsaturated and aromatic rings. Carbocycle includes bicyclicmolecules in which one, two or three or more atoms are shared betweenthe two rings. The term “fused carbocycle” refers to a bicycliccarbocycle in which each of the rings shares two adjacent atoms with theother ring. Each ring of a fused carbocycle may be selected fromsaturated, unsaturated and aromatic rings. In an exemplary embodiment,an aromatic ring, e.g., phenyl, may be fused to a saturated orunsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Anycombination of saturated, unsaturated and aromatic bicyclic rings, asvalence permits, is included in the definition of carbocyclic. Exemplary“carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane,1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene,bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fusedcarbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene,bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene andbicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one ormore positions capable of bearing a hydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R³⁴,wherein R³⁴ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR³⁵ whereinR³⁵ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O— heterocycle.Ethers include “alkoxyalkyl” groups, which may be represented by thegeneral formula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocyclyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to an “aryl”group or moiety implicitly includes both substituted and unsubstitutedvariants.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R³⁶ and R³⁷ independently represent hydrogen or hydrocarbyl,such as alkyl, or R³⁶ and R³⁷ taken together with the interveningatom(s) complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R³⁸, wherein R³⁸ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R³⁹,wherein R³⁹ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR⁴⁰ or—SC(O)R⁴⁰ wherein R¹⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁴¹ and R⁴² independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R⁴¹ taken together with R⁴² andthe intervening atom(s)complete a heterocycle having from 4 to 8 atomsin the ring structure.

The term “protecting group” refers to a group of atoms that, whenattached to a reactive functional group in a molecule, mask, reduce orprevent the reactivity of the functional group. Typically, a protectinggroup may be selectively removed as desired during the course of asynthesis. Examples of protecting groups can be found in Greene andWuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley& Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogenprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated (esterified) or alkylated such as benzyl and tritylethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers (e.g., TMS or TIPS groups), glycol ethers, such as ethyleneglycol and propylene glycol derivatives and allyl ethers.

In the pictorial representation of the compounds given through thisapplication, a thickened tapered line (

) indicates a substituent which is above the plane of the ring to whichthe asymmetric carbon belongs and a dotted line (

) indicates a substituent which is below the plane of the ring to whichthe asymmetric carbon belongs.

In certain embodiments, compounds of the invention may be racemic. Incertain embodiments, compounds of the invention may be enriched in oneenantiomer. For example, a compound of the invention may have greaterthan about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70%ee, about 80% ee, about 90% ee, or even about 95% or greater ee. Incertain embodiments, compounds of the invention may have more than onestereocenter. In certain such embodiments, compounds of the inventionmay be enriched in one or more diastereomer. For example, a compound ofthe invention may have greater than about 30% de, about 40% de, about50% de, about 60% de, about 70% de, about 80% de, about 90% de, or evenabout 95% or greater de.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one enantiomer of a compound (e.g., of Formula(I)). An enantiomerically enriched mixture may comprise, for example, atleast about 60 mol percent of one enantiomer, or more preferably atleast about 75, about 90, about 95, or even about 99 mol percent. Incertain embodiments, the compound enriched in one enantiomer issubstantially free of the other enantiomer, wherein substantially freemeans that the substance in question makes up less than about 10%, orless than about 5%, or less than about 4%, or less than about 3%, orless than about 2%, or less than about 1% as compared to the amount ofthe other enantiomer, e.g., in the composition or compound mixture. Forexample, if a composition or compound mixture contains about 98 grams ofa first enantiomer and about 2 grams of a second enantiomer, it would besaid to contain about 98 mol percent of the first enantiomer and onlyabout 2% of the second enantiomer.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one diastereomer of a compound (e.g., of Formula(I)). A diastereomerically enriched mixture may comprise, for example,at least about 60 mol percent of one diastereomer, or more preferably atleast about 75, about 90, about 95, or even about 99 mol percent.

The term “subject” to which administration is contemplated includes, butis not limited to, humans (i.e., a male or female of any age group,e.g., a pediatric subject (e.g., infant, child, adolescent) or adultsubject (e.g., young adult, middle-aged adult or senior adult)) and/orother primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals,including commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs; and/or birds, including commerciallyrelevant birds such as chickens, ducks, geese, quail, and/or turkeys.Preferred subjects are humans.

As used herein, a therapeutic that “prevents” a disorder or conditionrefers to a compound that, in a statistical sample, reduces theoccurrence of the disorder or condition in the treated sample relativeto an untreated control sample, or delays the onset or reduces theseverity of one or more symptoms of the disorder or condition relativeto the untreated control sample.

The term “treating” includes prophylactic and/or therapeutic treatments.The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the subject of one or more of the disclosedcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thesubject) then the treatment is prophylactic (i.e., it protects thesubject against developing the unwanted condition), whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “prodrug” is intended to encompass compounds which, underphysiologic conditions, are converted into the therapeutically activeagents of the present invention (e.g., a compound of Formula (I)). Acommon method for making a prodrug is to include one or more selectedmoieties which are hydrolyzed under physiologic conditions to reveal thedesired molecule. In other embodiments, the prodrug is converted by anenzymatic activity of the subject. For example, esters or carbonates(e.g., esters or carbonates of alcohols or carboxylic acids) arepreferred prodrugs of the present invention. In certain embodiments,some or all of the compounds of Formula (I) in a formulation representedabove can be replaced with the corresponding suitable prodrug, e.g.,wherein a hydroxyl in the parent compound is presented as an ester or acarbonate or carboxylic acid.

An “effective amount”, as used herein, refers to an amount that issufficient to achieve a desired biological effect. A “therapeuticallyeffective amount”, as used herein refers to an amount that is sufficientto achieve a desired therapeutic effect. For example, a therapeuticallyeffective amount can refer to an amount that is sufficient to improve atleast one sign or symptom of cancer.

A “response” to a method of treatment can include a decrease in oramelioration of negative symptoms, a decrease in the progression of adisease or symptoms thereof, an increase in beneficial symptoms orclinical outcomes, a lessening of side effects, stabilization ofdisease, partial or complete remedy of disease, among others.

The present invention provides compounds of Formula (I):

or a pharmaceutically acceptable salt and/or prodrug thereof, wherein

X is O, NR⁷ or CR⁷R⁸;

Y is O or S;

Z is NR¹⁹, O or S;

Het is heterocyclyl or heteroaryl;

R^(1a) is selected from H, halo, hydroxy, cyano, azido, amino,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₆acyloxy,—O—C(O)—O—C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, and C₂₋₆alkynyl; and

R^(1b) is selected from H, halo, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,amino-C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl; or

R^(1a) and R^(1b), together with the carbon atom to which they areattached, form a C═CH₂ or C═C(H)C₁₋₆alkyl;

R^(2a) is selected from H, halo, hydroxy, cyano, azido, amino,C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₆acyloxy,—O—C(O)—O—C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, and C₂₋₆alkynyl;

R^(2b) is selected from H, halo, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,amino-C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl; or

R^(2a) and R^(2b), together with the carbon atom to which they areattached, form a C═CH₂ or C═C(H)C₁₋₆alkyl;

R³ is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and—(CH₂)—C(O)OR₉;

R⁴ is selected from heteroaryl, alkyl, —C(O)OR⁹, —C(O)NR¹¹R¹²,—S(O)₂R¹⁰, —P(O)(OR¹¹)(OR¹²), and —P(O)(OR¹¹)(NR¹³R¹⁵);

R⁵ is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl,aralkyl, heteroaralkyl, and —C(O)OR⁹;

R⁶ is selected from —C(O)OR^(S) and —P(O)(OR¹¹)(OR¹²);

each R⁷ and R⁸ is H

R⁹ is independently selected from H, alkyl, acyloxyalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, and heteroaralkyl, and—(CHR¹³)_(m)—Z—C(O)—R¹⁴;

each R¹⁰ is independently selected from alkyl, alkenyl, alkynyl, amino,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,aralkyl, heteroaryl, and heteroaralkyl; and

each R¹¹ and R¹² is independently selected from H, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl and —(CHR¹³)_(m)—Z—C(O)—R¹⁴; or

R¹¹ and R¹², together with the atoms to which they are attached, form a5- to 7-membered heterocyclyl; and

each R¹³ is independently H or alkyl;

each R¹⁴ is independently selected from alkyl, aminoalkyl, heterocyclyl,and heterocyclylalkyl;

R¹⁵ is selected from alkyl, aralkyl, —C(R¹⁶)(R¹⁷)—C(O)O—R¹⁸; each R¹⁶and R¹⁷ are selected from H, alkyl, amino-alkyl, hydroxy-alkyl,mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl,heterocyclylalkyl, heteroaralkyl, and —(CH₂)C(O)OR⁹;

R¹⁸ is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl,amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl;

R¹⁹ is H or alkyl, preferably H; and

m is 1 or 2;

provided that either R⁴ is tetrazolyl, or R⁵ is aralkyl orheteroaralkyl, or both.

In certain embodiments, R^(1a) is selected from H, halo, hydroxy, cyano,azido, amino, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₆acyloxy,C₁₋₆alkoxy, C₂₋₆alkenyl, and C₂₋₆alkynyl. In certain embodiments, R¹a isfluoro, chloro or bromo, preferably fluoro. In certain embodiments,R^(1a) is C₁₋₆alkoxy. In certain embodiments, R^(1a) is C₁₋₆alkyl. Incertain embodiments, R^(1a) is hydroxy. In certain embodiments, R^(1a)is ethynyl or vinyl. In certain embodiments, R^(1a) is cyano. In certainembodiments, R^(1a) is azido. In certain embodiments, R^(1a) is amino.In certain embodiments, R^(1a) is hydrogen.

In certain embodiments, R^(2a) is selected from H, halo, hydroxy, cyano,azido, amino, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₆acyloxy,C₁₋₆alkoxy, C₂₋₆alkenyl, and C₂₋₆alkynyl. In other embodiments, R^(2a)is fluoro, chloro, or bromo, preferably fluoro. In certain embodiments,R^(2a) is C₁₋₆alkoxy. In certain embodiments, R^(2a) is C₁₋₆alkyl. Incertain embodiments, R^(2a) is hydroxy. In certain embodiments, R^(2a)iscyano. In certain embodiments, R^(2a) is azido. In certainembodiments, R^(2a) is amino. In certain embodiments, R^(2a) isC₁₋₆acyloxy.

In certain embodiments, R^(1b) is H. In other embodiments, R^(1b) isfluoro. In other embodiments, R^(1b) is C₁₋₆alkyl. In certainembodiments, R^(2b) is H. In other embodiments, R^(2b) is fluoro. Inother embodiments, R^(2b) is C₁₋₆alkyl.

In certain embodiments, R^(1a) is fluoro and R^(1b) is H. In otherembodiments, R^(2a) is fluoro and R^(2b) is H. In certain embodiments,R^(1a) and R^(1b) are each fluoro. In other embodiments, R^(2a) andR^(2b) are each fluoro. In some embodiments, R^(1a) is fluoro and R^(2a)is C₁₋₆alkoxy. In some embodiments, R^(1a) is fluoro and R^(2a) isC₁₋₆alkyl, such as methyl or ethyl. In certain embodiments, R^(2a) ishydroxy and R^(2b) is methyl.

In certain embodiments, R^(1a) is fluoro and R^(2a) is hydroxy. Incertain embodiments, R^(1a) is chloro and R^(2a) is hydroxy. In certainembodiments, R^(1a) is hydroxy and R^(2a) is hydrogen. In certainembodiments, R^(1a) is fluoro and R^(2a) is hydrogen. In certainembodiments, R^(1a) is hydroxy and R^(2a) is C₁₋₆alkoxy, such asmethoxy. In certain embodiments, R^(1a) is hydroxy and R^(2a) is fluoro.In certain embodiments, R^(1a) is hydroxy and R^(2a) and R^(2b),together with the carbon atom to which they are attached, form anethynyl. In certain embodiments, R^(1a) is hydroxy and R^(2a) isC₁₋₆alkyl, such as methyl. In certain embodiments, R^(1a) is fluoro,R^(2a) is fluoro and R^(2a) is hydroxy. In certain embodiments, R^(1a)is hydroxy and R^(2a) is hydroxyl and R^(2b) is C₁₋₆alkynyl, such asethynyl. In certain embodiments, R^(1a) is hydroxy and R^(2a) isC₁₋₆alkynyl, such as ethynyl. In certain embodiments, R^(1a) is hydroxyand R^(2a) is C₂₋₆alkenyl. In certain embodiments, R^(1a) is hydroxy andR^(2a) is amino. In certain embodiments, R^(1a) is hydroxy and R^(2a) isazido. In certain embodiments, R^(1a) is azido and R^(2a) is hydroxy. Incertain embodiments, R^(1a) is C₁₋₆alkyl, such as methyl, and R^(2a) ishydroxy.

In certain embodiments, the compound of Formula (I) has the followingstructure:

In certain embodiments, R^(1a) is in the α-configuration. In some suchembodiments, the compound of Formula (I) has the structure (IA):

In other embodiments, R^(1a) is in the β-configuration. In some suchembodiments, the compound of Formula (I) has the structure (IB):

In certain embodiments, R^(2a) is in the α-configuration. In some suchembodiments, the compound of Formula (I) has the structure (IC):

In other embodiments, R^(2a) is in the β-configuration. In someembodiments, the compound of Formula (I) has the structure (ID):

In certain embodiments, the compound of Formula (I) has the structure(IE):

In certain embodiments, R³ is alkyl, and the alkyl is unsubstituted orsubstituted, e.g., with one or more substituents selected from halo, CN,NO₂, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl,thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate,urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl,phosphoryl, phosphate, phosphonate, and phosphinate. In certainembodiments, the substituents are selected from halo, CN, azido, alkoxy,carbonyl, amino, amido, and alkoxycarbonyl. In certain preferredembodiments, R³ is H. In other preferred embodiments, R³ isunsubstituted C₁₋₆alkyl.

In certain embodiments, R⁴ is heteroaryl. In certain preferredembodiments, R⁴ is tetrazolyl.

In certain embodiments, R⁴ is selected from —C(O)OR⁹, —C(O)NR¹¹R¹²,—S(O)₂R¹⁰, and —P(O)(OR¹¹)(OR¹²). In some preferred embodiments, R⁴ is—C(O)OR⁹. In certain embodiments, R⁹ is H or C₁₋₆alkyl. In someembodiments, R⁴ is —C(O)NR¹¹R¹². In certain such embodiments, R¹¹ andR¹² are each alkyl, such as methyl. In alternative such embodiments, R¹¹is alkyl and R¹² is hydrogen. In other embodiments, R⁴ is alkylsubstituted with carboxyl or ester (e.g., alkoxycarbonyl).

In certain embodiments, R⁵ is selected from H, alkyl, cycloalkylalkyl,heterocyclylalkyl, aralkyl, and heteroaralkyl. In certain embodiments,R⁵ is H, aralkyl, or heteroaralkyl. For example, R⁵ can be—CH₂-pyridinyl, —CH₂-thiophenyl, benzyl or β-naphthyl. In certainembodiments, R⁴ is heteroaryl, such as tetrazolyl, R⁵ is unsubstitutedor substituted benzyl and R⁶ is —COOH.

In certain embodiments, Rs is selected from H, alkyl, cycloalkylalkyl,heterocyclylalkyl, aralkyl, and heteroaralkyl. In certain embodiments,R⁵ is selected from alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyland heteroaralkyl, and each is unsubstituted or substituted with one ormore substituents, e.g., selected from halo, CN, NO₂, azido, hydroxy,alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino,amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido,sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate,phosphinate, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl andheteroarylalkyl. In certain embodiments, the substituents are selectedfrom halo, CN, NO₂, azido, hydroxy, alkoxy, alkylthio, thioalkoxy,carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl,carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido,sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate, cycloalkyl,heterocyclyl, arylalkyl and heteroarylalkyl. In certain embodiments, thesubstituents are selected from halo, CN, azido, alkoxy, carbonyl, amino,amido, and alkoxycarbonyl. In other embodiments, the substitutents areselected from chloro, trifluoromethyl, trifluoromethoxy, phenyloxy,dimethylamido, methylsulfonyl, CN, and carboxylic acid. In somepreferred embodiments, R₅ is H or aralkyl.

In some embodiments, R⁵ is aralkyl, e.g., wherein the aryl ring issubstituted or unsubstituted phenyl or naphthyl. In other embodiments,R⁵ is heteroaralkyl, e.g., wherein the heteroaryl ring is selected fromsubstituted or unsubstituted benzofuranyl, benzothienyl, benzothiazolyl,pyridyl, thienyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, andoxadiazolyl.

In some embodiments, R⁵ is aralkyl or heteroaralkyl, wherein the aryl orheteroaryl ring, respectively, is unsubstituted or substituted with oneor more substituents, e.g., selected from halo, CN, OH, alkyl, alkenyl,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylsulfonyl, sulfonamido, amido, amino, carboxyl, ester (e.g., loweralkyl ester), heterocyclyl, heteroaryl, aryl, aralkyl, andheteroaralkyl. In certain embodiments, the substituents are selectedfrom halo, CN, OH, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido,amino, carboxyl, ester (e.g., lower alkyl ester), heteroaryl, aryl,aralkyl, and heteroaralkyl. In certain such embodiments, thesubstituents on the aryl or heteroaryl ring of the aralkyl orheteroaralkyl, respectively, are selected from halo, CN, haloalkyl,haloalkoxy, carboxy, ester (e.g., lower alkyl ester), and aryl. In othersuch embodiments, the substituents on the aryl or heteroaryl ring of thearalkyl or heteroaralkyl, respectively, are selected from tetrazolyl,substituted or unsubstituted phenyl, or substituted or unsubstitutedbenzyl.

In certain embodiments, R6 is —C(O)OR₉. In some embodiments, R₉ is H orC₁₋₆alkyl. In other embodiments, R₆ is —P(O)(OR₁₁)(OR₁₂), and R₁₁ andR₁₂ are each H. In certain embodiments, R₇ is H or C₁₋₆alkyl. In certainembodiments, R₈ is H. In certain embodiments, R₉ is H or C₁₋₆alkyl, suchas methyl or ethyl. In certain embodiments, R₁₁ and R₁₂ are each H.

In certain embodiments, each R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ isindependently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, and heteroaralkyl, and each is unsubstituted or substituted,e.g., with one or more selected from halo, CN, NO₂, azido, hydroxy,alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino,amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido,sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, andphosphinate. In some embodiments, the substituents are selected fromhalo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

In certain embodiments, X is O. In certain embodiments, Y is O. Incertain embodiments, the Y-bearing substituent is in theR-configuration. In other embodiments, the Y-bearing substituent is inthe S-configuration. In certain embodiments, Z is O. In otherembodiments, Z is NH.

In certain embodiments, Het is a nitrogen-containing heterocyclyl orheteroaryl. In certain embodiments, Het is attached via a nitrogen atom.In other, embodiments, Het is attached via a carbon atom. In someembodiments, Het is a 5- to 8-membered monocyclic or 5- to 10-memberedbicyclic heteroaryl and is unsubstituted or substituted, e.g., with oneor more substituents selected from halo, CN, NO₂, azido, hydroxy,alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, cyclothioalkyl,amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea,sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl,phosphate, phosphonate, and phosphinate. In certain embodiments, thesubstituents are selected from halo, CN, NO₂, azido, hydroxy, alkoxy,alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino,amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido,sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, andphosphinate. In certain embodiments, the substituents are selected fromhalo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. Incertain preferred embodiments, Het is selected from purinyl,imidazopyrimidinyl, and pyrrolopyrimidinyl. In other embodiments, Het issubstituted with one or two substituents independently selected fromhalo, aralkyl, amino, azido and hydroxy. In some embodiments, Het issubstituted with one halo and one amino substituent. In certainpreferred embodiments, Het is

In certain embodiments, Het is selected from

In certain embodiments,

Het is

In certain embodiments, Het is selected from

In certain embodiments, Het is a group of formula (i) through (xiv)below:

wherein:

R^(u) is hydrogen, halo, cyano, —NH₂, —NHR²⁰, —NHCOR²⁰, —NR²⁰R²¹, —R²⁰,—SR²⁰, —OH, and —OR²⁰.

R^(w) is hydrogen, halo, —NHR²², —NR²²R²³, —R²², —OH, and —OR²²;

R^(v) and R^(x) are independently hydrogen, halo, haloC₁₋₆alkyl, —NH₂,—NHR²⁴, —NR²⁴R²⁵, —R²⁴, —SR²⁴, cyano, —OH, —OR²⁴, —SO₂R²⁴,—C₁₋₆alkyleneNH₂, —C₁₋₆alkyleneNHR²⁴, —C₁₋₆alkyleneNR²⁴R²⁵, —R²⁴,—C₁₋₆alkyleneSR²⁴, —C₁₋₆alkyleneOH, —C₁₋₆alkyleneOR²⁴,—C₁₋₆alkyleneSO₂R²⁴,

R^(s) and R^(t) are independently hydrogen, halo, or C₁₋₆alkyl; andwherein:

R²⁰, R²¹, R²², R²³, R²⁴ and R²⁵ are independently optionally substitutedC₁₋₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylC₁₋₆alkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl,optionally substituted aryl, optionally substituted arylC₁₋₆alkyl,optionally substituted heteroaryl, or optionally substitutedheteroarylC₁₋₆alkyl; or R²⁰ and R²¹, R²² and R²³, and R²⁴ and R²⁵together with the nitrogen to which they are attached form an optionallysubstituted nitrogen-containing heterocyclyl.

In certain embodiments,

represents

In certain embodiments,

represents

In certain embodiments,

represents

In certain embodiments,

represents

In certain embodiments,

represents

wherein

each R_(A) is independently selected from halo, CN, OH, alkyl,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy (e.g.,substituted or unsubstituted benzyloxy), alkylsulfonyl, sulfonamido,amido, amino, hydroxycarbonyl, alkoxycarbonyl, heterocyclyl, heteroaryl,aryl, aralkyl, and heteroaralkyl; and

k is 1, 2, or 3.

In certain embodiments, RA is selected from halo, CN, OH, alkyl,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy (e.g.,substituted or unsubstituted benzyloxy), alkylsulfonyl, sulfonamido,amido, amino, hydroxycarbonyl, alkoxycarbonyl, heteroaryl, aryl,aralkyl, and heteroaralkyl. In certain embodiments, R_(A) is selectedfrom pyridyl, pyrazolyl, pyrrolidinonyl, azapanonyl, morpholinonyl,piperazonyl, tetrahydropyrimidinonyl, phenyl, and benzyloxy.

Further Embodiments

In the following numbered embodiments, unless otherwise specified:

-   C₁₋₆alkyl is unsubstituted;-   C₁₋₆alkyl of C₁₋₆alkyloxy is unsubstituted;-   haloC₁₋₆alkyl is C₁₋₆alkyl substituted with one to five halo atoms;-   haloC₁₋₆alkyloxy is C₁₋₆alkyloxy substituted with one to five halo    atoms;-   C₂₋₆alkenyl is unsubstituted;-   C₂₋₆alkynyl is unsubstituted;-   C₁₋₆alkylene group is unsubstituted; C₂₋₆alkenylene group is    unsubstituted;-   optionally substituted C₁₋₆alkyl is optionally substituted with one    or two substituents independently selected from hydroxy,    C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂,    —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, optionally substituted carbocyclyl,    optionally substituted aryl, optionally substituted heteroaryl, and    optionally substituted heterocyclyl;-   carbocyclyl is an unsubstituted saturated or partially unsaturated    mono or bicyclic ring containing 3 to 10 carbon atoms;-   optionally substituted carbocyclyl is optionally substituted with    one, two, or three substituents independently selected from    C₁₋₆alkyl, halo, hydroxy, or C₁₋₆alkoxy;-   aryl is phenyl or naphthyl;-   optionally substituted aryl is optionally substituted with one, two,    or three substituents independently selected from hydroxy,    C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂,    —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, optionally substituted carbocyclyl,    aryl [optionally substituted with one, two, or three substituents    independently selected from hydroxy, C₁₋₆alkyloxy, halo,    haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂, —NH(C₁₋₆alkyl), and    —N(C₁₋₆alkyl)₂], heteroaryl [optionally substituted with one, two,    or three substituents independently selected from hydroxy,    C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂,    —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂], and heterocyclyl [optionally    substituted with one, two, or three substituents independently    selected from hydroxy, C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl,    haloC₁₋₆alkyloxy, cyano, —NH₂, —NH(C₁₋₆alkyl), —N(unsubstitued    C₁₋₆alkyl)₂];-   heteroaryl is an unsubstituted five to ten membered or five to six    membered aromatic ring containing one to four or one to three    heteroatoms independently selected from N, O, and S, the remaining    ring atoms being carbon;-   optionally substituted heteroaryl is a five to ten membered aromatic    ring containing one to four heteroatoms independently selected from    N, O, and S, the remaining ring atoms being carbon, that is    optionally substituted with one, two, or three substituents    independently selected from hydroxy, C₁₋₆alkyloxy, halo,    haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂, —NH(C₁₋₆alkyl),    —N(C₁₋₆alkyl)₂, optionally substituted carbocyclyl, aryl [optionally    substituted with one, two, or three substituents independently    selected from hydroxy, C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl,    haloC₁₋₆alkyloxy, cyano, —NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂],    heteroaryl [optionally substituted with one, two, or three    substituents independently selected from hydroxy, unsubstituted    C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂,    —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂], and heterocyclyl [optionally    substituted with one, two, or three substituents independently    selected from hydroxy, C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl,    haloC₁₋₆alkyloxy, cyano, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂];    heterocyclyl is an unsubstituted monocyclic, saturated or partially    unsaturated 4 to 8 membered ring containing one to three heteroatoms    independently selected from N, O, S, SO, and SO₂ and optionally    contains one or two CO, the remaining atoms in the ring being carbon    that is optionally fused to phenyl or 5 to 6 membered carbocyclyl or    5 or 6 heteroaryl ring;-   nitrogen-containing heterocyclyl is a heterocyclyl ring that has at    least a nitrogen atom;-   optionally substituted heterocyclyl is heterocyclyl that is    optionally substituted with one, two, or three substituents    independently selected from hydroxy, C₁₋₆alkyloxy, halo,    haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂, —NH(C₁₋₆alkyl),    —N(C₁₋₆alkyl)₂, optionally substituted carbocyclyl, aryl [optionally    substituted with one, two, or three substituents independently    selected from hydroxy, C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl,    haloC₁₋₆alkyloxy, cyano, —NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂],    heteroaryl [optionally substituted with one, two, or three    substituents independently selected from hydroxy, C₁₋₆alkyloxy,    halo, haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂, —NH(C₁₋₆alkyl),    —N(C₁₋₆alkyl)₂], and heterocyclyl optionally substituted with one,    two, or three substituents independently selected from hydroxy,    C₁₋₆alkyloxy, halo, haloC₁₋₆alkyl, haloC₁₋₆alkyloxy, cyano, —NH₂,    —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂]; optionally substituted carbocyclyl    C₁₋₆alkyl is optionally substituted carbocyclyl attached via    C₁₋₆alkyl;-   optionally substituted heterocyclylC₁₋₆alkyl is optionally    substituted heterocyclyl attached via C₁₋₆alkyl;-   optionally substituted arylC₁₋₆alkyl is optionally substituted aryl    attached via C₁₋₆alkyl; and-   optionally substituted heteroarylC₁₋₆alkyl is optionally substituted    heteroaryl attached via C₁₋₆alkyl.

Embodiment 1

In embodiment 1, the compound of Formula (I) is as defined in theSummary.

In a subembodiment of embodiment 1, the compounds of Formula (I) arethose wherein when R⁵ is hydrogen, R^(1a) and R^(1b) are independentlyhydrogen, hydroxy, halo, C₁-C₃alkyl, C₁-C₃alkoxy, C₂-C₃alkenyl, orC₂-C₃alkynyl, R^(2a), R^(2b) and R³ are hydrogen, then Het is not2,4-dioxo-3,4-dihydropyrimidinyl,2,4-dioxo-3,4,5,6-tetrahydropyrimidinyl, 6-oxopurinyl,6-amino-9H-purin-9-yl, or oxopyrimidinyl wherein each ring of theaforementioned ring is optionally substituted with C₁₋₆alkyl.

Embodiment 2

In embodiment 2, the compounds of embodiment 1 and subembodimentscontained therein are those wherein R⁵ is phenylC₁₋₆alkyl ornaphthylC₁₋₆alkyl, preferably benzyl, wherein phenyl and naphthyl areoptionally substituted with one, two, or three substituentsindependently selected from —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkylsubstituted with one to five fluoro, —OC₁₋₆alkyl (substituted with oneto five fluoro), —C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl,—C₂₋₆alkenylene-CO₂H, —OC₁₋₆alkylene-CO₂H, —OC₁₋₆alkylene-CO₂C₁₋₆alkyl,—C₁₋₆alkyl substituted with one or two hydroxy, —OC₁₋₆alkyl substitutedwith one or two hydroxy, —C₁₋₆alkyl substituted with one or two—OC₁₋₆alkyl, —OC₁₋₆alkyl (substituted with one or two —OC₁₋₆alkyl),—CO₂H, —COOC₁₋₆alkyl, hydroxy, halo, nitro, —PO₃H₂, cyano, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —CONR^(e)R^(f) (where R^(e) and R^(f)are independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H,—C₁₋₆alkylene-CO₂C₁₋₆alkyl, or —C₁₋₆alkylene-substituted with one or twosubstituents independently selected from hydroxy, NH₂, —NHC₁₋₆alkyl or—N(C₁₋₆alkyl)₂), —SO₂(C₁₋₆alkyl), —SO₂NR^(g)R^(h) (where R^(g) and R^(h)are independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H, or—C₁₋₆alkylene-CO₂C₁₋₆alkyl), —SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂NHCOR^(j)(where R^(j) is —C₁₋₆alkyl, —NHC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂), phenyl,—C₁₋₆alkylenephenyl, phenoxy, —OC₁₋₆alkylenephenyl, 5- or 6-memberedmonocyclic heteroaryl containing one to four heteroatoms independentlyselected from O, N, and S [wherein the heteroaryl ring is optionallysubstituted with one, two, or three substituents independently selectedfrom hydroxyl, halo, CN, —CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl,—C₁₋₆alkyl (substituted with one to five fluoro), —OC₁₋₆alkyl(substituted with one to five fluoro), —C₁₋₆alkylene-CO₂H,—C₁₋₆alkylene-CO₂C₁₋₆alkyl, tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂,—SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)2, —CONH₂, —CONHC₁₋₆alkyl, and—CON(C₁₋₆alkyl)₂], —OR^(i), —C₁₋₆alkylene-R^(i), —OC₁₋₆alkylene-R^(i),—SR^(i), —SC₁₋₆alkylene-R^(i), heterocyclyl, —C₁₋₆alkyleneheterocyclyl,—OC₁₋₆alkyleneheterocyclyl, —SC₁₋₆alkyleneheterocyclyl,—CONR^(m)C₁₋₆alkyleneheterocyclyl, —NR^(m)COC₁₋₆alkyleneNR^(o)R^(p),—NR^(m)COheterocyclyl, —NR^(m)COC₁₋₆alkyleneheterocyclyl,—COheterocyclyl, —CONR^(m)R^(i), —CONR^(m)C₁₋₆alkylene-R^(i),—OCONR^(m)R^(m), —NR^(m)—COR^(y), —NR^(m)—CO—NR^(m)R^(y),—NR^(m)—SO₂—R^(y), —NR^(m)—SO₂—NR^(m)R^(y), and —CONHSO₂R^(z); wherein:

each R^(m) is hydrogen or —C₁₋₆alkyl;

R^(o), R^(p), and R^(y) are independently hydrogen or —C₁₋₆alkyl;

R^(z) is —C₁₋₆alkyl, —NHC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂;

phenyl by itself or as part of —C₁₋₆alkylenephenyl, phenoxy, or—OC₁₋₆alkylenephenyl is optionally substituted with one, two, or threesubstituents independently selected from hydroxyl, halo, CN, —CO₂H,—COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl substituted with oneto five fluoro, —OC₁₋₆alkyl (substituted with one to five fluoro),—C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl, tetrazolyl,—SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂,—CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂;

each R^(i) is independently 5- or 6-membered monocyclic heteroarylcontaining one to four heteroatoms independently selected from O, N, andS and wherein the heteroaryl ring is optionally substituted with one,two, or three substituents independently selected from hydroxyl, halo,CN, —CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkylsubstituted with one to five fluoro, —OC₁₋₆alkyl (substituted with oneto five fluoro), —C₁₋₆alkylene-CO₂H, and —C₁₋₆alkylene-CO₂C₁₋₆alkyl,tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂,—CONH₂, —CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂;

heterocyclyl by itself or as part of —C₁₋₆alkyleneheterocyclyl,—OC₁₋₆alkyleneheterocyclyl, —SC₁₋₆alkyleneheterocyclyl,—CONR^(m)C₁₋₆alkyleneheterocyclyl, —NR^(m)COC₁₋₆alkyleneheterocyclyl,—COheterocyclyl, or —NR^(m)COheterocyclyl is optionally substituted withone, two, or three substituents independently selected from hydroxy,halo, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, or —C₁₋₆alkyl (substitutedwith hydroxy or —OC₁₋₆alkyl).

Embodiment 3

In embodiment 3, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is phenylC₁₋₆alkyl ornaphthylC₁₋₆alkyl, preferably benzyl, wherein phenyl and naphthyl (alsoreferred to below as R⁵ phenyl and naphthyl rings respectivelyl) areoptionally substituted, preferably substituted, with one or twosubstituents independently selected from —C₁₋₆alkyl, —OC₁₋₆alkyl,—C₁₋₆alkyl substituted with one to five fluoro, —OC₁₋₆alkyl substitutedwith one to five fluoro, —C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl,—OC₁₋₆alkylene-CO₂H, —OC₁₋₆alkylene-CO₂C₁₋₆alkyl, —C₁₋₆alkyl substitutedwith one or two hydroxy, —OC₁₋₆alkyl substituted with one or twohydroxy, —C₁₋₆alkyl substituted with one or two substituentsindependently selected from —OC₁₋₆alkyl, —OC₁₋₆alkyl (substituted withone or two —OC₁₋₆alkyl), —CO₂H, —COOC₁₋₆alkyl, halo, hydroxy, nitro,—PO₃H₂, cyano, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —CONR^(e)R^(f)(where R^(e) and R^(f) are independently hydrogen, —C₁₋₆alkyl,—C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl, or —C₁₋₆alkylsubstituted with one or two substituents independently selected fromhydroxyl, NH₂, —NHC₁₋₆alkyl or —N(C₁₋₆alkyl)₂), —SO₂(C₁₋₆alkyl),—SO₂NR^(g)R^(h) (where R^(g) and R^(h) are independently hydrogen,—C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H, or —C₁₋₆alkylene-CO₂C₁₋₆alkyl),—SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂NHCOR^(j) (where R^(j) is —C₁₋₆alkyl,—NHC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂), phenyl, phenoxy, benzyl,—OC₁₋₆alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containingone to four heteroatoms independently selected from O, N, and S [whereinthe heteroaryl ring is optionally substituted with one, two, or threesubstituents independently selected from hydroxyl, halo, CN, —CO₂H,—COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl substituted with oneto five fluoro, —OC₁₋₆alkyl (wherein alkyl is substituted with one tofive fluoro), —C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl,tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂,—CONH₂, —CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂], —OR', —C₁₋₆alkylene-W,—OC₁₋₆alkylene-R^(i), —SR^(i), —SC₁₋₆alkylene-R^(i), heterocyclyl,—C₁₋₆alkyleneheterocyclyl, —OC₁₋₆alkyleneheterocyclyl,—SC₁₋₆alkyleneheterocyclyl, —CONR^(m)C₁₋₆alkyleneheterocyclyl,—NR^(m)COC₁₋₆alkyleneNR^(o)R^(p), —NR^(m)CO-heterocyclyl,—NR^(m)COC₁₋₆alkyleneheterocyclyl, —COheterocyclyl, —CONR^(m)R^(i),—CONR^(m)alkylene-R^(i), and —CONHSO₂R^(z); and

additionally the R⁵ phenyl and naphthyl rings are optionally substitutedwith a third substituent selected from —C₁₋₆alkyl, —C₁₋₆alkyl (whereinalkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl, —OC₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), halo, CN, —NH₂,and hydroxy; wherein:

each R^(m) is hydrogen or —C₁₋₆alkyl;

R^(o) and R^(p) are independently hydrogen or —C₁₋₆alkyl;

R^(z) is —C₁₋₆alkyl, —NHC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂,

phenyl by itself or as part of phenoxy, benzyl, or —OC₁₋₆alkylenephenylis optionally substituted with one, two, or three substituentsindependently selected from hydroxyl, halo, CN, —CO₂H, —COOC₁₋₆alkyl,—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to five fluoro,—OC₁₋₆alkyl (substituted with one to five fluoro), —C₁₋₆alkylene-CO₂H,—C₁₋₆alkylene-CO₂C₁₋₆alkyl, tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂,—SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂, —CONHC₁₋₆alkyl, and—CON(C₁₋₆alkyl)₂;

each R^(i) is independently 5- or 6-membered monocyclic heteroarylcontaining one to four heteroatoms independently selected from O, N, andS and wherein the heteroaryl ring is optionally substituted with one,two, or three substituents independently selected from hydroxyl, halo,CN, —CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkylsubstituted with one to five fluoro, —OC₁₋₆alkyl (substituted with oneto five fluoro), —C₁₋₆alkylene-CO₂H, and —C₁₋₆alkylene-CO₂C₁₋₆alkyl,tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)2,—CONH₂, —CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂;

heterocyclyl by itself or as part of —C₁₋₆alkyleneheterocyclyl,—OC₁₋₆alkyleneheterocyclyl, —SC₁₋₆alkyleneheterocyclyl,—CONR^(m)C₁₋₆alkylene-heterocyclyl, —NR^(m)COheterocyclyl,—COheterocyclyl, or —NR^(m)COC₁₋₆alkyleneheterocyclyl is optionallysubstituted with one, two, or three substituents independently selectedfrom hydroxy, halo, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, or—C₁₋₆alkyl (substituted with hydroxy or —OC₁₋₆alkyl).

Embodiment 4

In embodiment 4, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is phenylC₁₋₆alkyl, preferablybenzyl, wherein phenyl is substituted with one substituent at the metaor para position, preferably para, to the carbon atom of the phenyl ringthat is attached to —C₁₋₆alkyl in —C₁₋₆alkylphenyl or —CH₂— in benzylrespectively, which one substituent is selected from —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to five fluoro, —OC₁₋₆alkyl(substituted with one to five fluoro), —C₁₋₆alkylene-CO₂H,-C₁₋₆alkylene-CO₂C₁₋₆alkyl, —OC₁₋₆alkylene-CO₂H,—OC₁₋₆alkylene-CO₂C₁₋₆alkyl, —CO₂H, —COOC₁₋₆alkyl, halo, hydroxy, cyano,nitro, —PO₃H₂, —CONR^(e)R^(f) (where R^(e) and R^(f) are independentlyhydrogen, —C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl, or—C₁₋₆alkyl substituted with one or two substituents independentlyselected from hydroxy, NH₂, —NHC₁₋₆alkyl or —N(C₁₋₆alkyl)₂),—SO₂(C₁₋₆alkyl), —SO₂NR^(g)R^(h) (where R^(e) and R^(h) areindependently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H, or—C₁₋₆alkylene-CO₂C₁₋₆alkyl), phenyl, phenoxy, benzyl, benzyloxy, 5- or6-membered monocyclic heteroaryl containing one to four heteroatomsindependently selected from O, N, and S [wherein the heteroaryl ring isoptionally substituted with one, two, or three substituentsindependently selected from hydroxy, halo, CN, —CO₂H, —COOC₁₋₆alkyl,—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl (wherein alkyl is substituted withone to five fluoro), —OC₁₋₆alkyl (wherein alkyl is substituted with oneto five fluoro), —C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl,tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂,—CONH₂, —CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂], —OR^(i),—C₁₋₆alkylene-R^(i), —OC₁₋₆alkylene-R^(i), —SR^(i),—SC₁₋₆alkylene-R^(i), heterocyclyl, —C₁₋₆alkyleneheterocyclyl,—OC₁₋₆alkyleneheterocyclyl, —SC₁₋₆alkyleneheterocyclyl,—CONR^(m)C₁₋₆alkyleneheterocyclyl, —NR^(m)COC₁₋₆alkyleneNR^(o)R^(p),—NR^(m)COheterocyclyl, —NR^(m)COC₁₋₆alkyleneheterocyclyl,—COheterocyclyl, —CONR^(m)R^(i), and —CONR^(m)alkylene-R^(i); and

the R⁵ phenyl ring is additionally optionally substituted with one ortwo substituents independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy; wherein

each R^(m) is hydrogen or —C₁₋₆alkyl;

R^(o) and R^(p) are independently hydrogen or —C₁₋₆alkyl;

phenyl by itself or as part of benzyl, phenoxy, or benzyloxy isoptionally substituted with one, two, or three substituentsindependently selected from hydroxyl, halo, CN, —CO₂H, —COOC₁₋₆alkyl,—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to five fluoro,—OC₁₋₆alkyl (substituted with one to five fluoro), —C₁₋₆alkylene-CO₂H,—C₁₋₆alkylene-CO₂C₁₋₆alkyl, tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂,—SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂, —CONHC₁₋₆alkyl, and—CON(C₁₋₆alkyl)₂;

each R^(i) is independently 5- or 6-membered monocyclic heteroarylcontaining one to four heteroatoms independently selected from O, N, andS and wherein the heteroaryl ring is optionally substituted with one,two, or three substituents independently selected from hydroxyl, halo,CN, —CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkylsubstituted with one to five fluoro, —OC₁₋₆alkyl (substituted with oneto five fluoro), —C₁₋₆alkylene-CO₂H, and —C₁₋₆alkylene-CO₂C₁₋₆alkyl,tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂,—CONH₂, —CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂;

heterocyclyl by itself or as part of —C₁₋₆alkyleneheterocyclyl,—OC₁₋₆alkyleneheterocyclyl, —SC₁₋₆alkyleneheterocyclyl,—CONR^(m)C₁₋₆alkyleneheterocyclyl, —NR^(m)COheterocyclyl,—COheterocyclyl, or —NR^(m)COC₁₋₆alkyleneheterocyclyl is optionallysubstituted with one, two, or three substituents independently selectedfrom hydroxy, halo, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, or—C₁₋₆alkyl (substituted with hydroxy or —OC₁₋₆alkyl).

Embodiment 5

In embodiment 5, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂phenyl or —(CH₂)₂phenyl,preferably —CH₂phenyl (benzyl) wherein phenyl is optionally substituted,preferably substituted, with one substituent at the meta or paraposition, preferably para, to the carbon atom of the phenyl ring that isattached to —C₁₋₆alkyl in —C₁₋₆alkylphenyl and —CH₂— in —CH₂phenyl(benzyl) respectively, which one substituent is selected from—OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to five fluoro, —OC₁₋₆alkyl(substituted with one to five fluoro), —C₁₋₆alkyl substituted withhydroxy, —C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl,—OC₁₋₆alkylene-CO₂H, —OC₁₋₆alkylene-CO₂C₁₋₆alkyl, —CO₂H, nitro,—COOC₁₋₆alkyl, halo, hydroxy, cyano, —CONR^(e)R^(f) (where R^(e) ishydrogen or —C₁₋₆alkyl and R^(f) is —C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H,—C₁₋₆alkylene-CO₂C₁₋₆alkyl, or —C₁₋₆alkyl substituted with one or twohydroxyl, —NH₂, —NHC₁₋₆alkyl or —N(C₁₋₆alkyl)₂), —SO₂(C₁₋₆alkyl),—SO₂NR^(g)R^(h) (where R^(g) is hydrogen or —C₁₋₆alkyl and R^(h) ishydrogen, —C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H, or—C₁₋₆alkylene-CO₂C₁₋₆alkyl), oxadiazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl,thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl orisoxazolyl (wherein each of the aforementioned heteroaryl rings isoptionally substituted with one or two substituents independentlyselected from C₁₋₆alkyl, halo, CN, —CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to five fluoro, —OC₁₋₆alkyl(substituted with one to five fluoro), tetrazolyl, —SO₂C₁₋₆alkyl,—SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂, —CONHC₁₋₆alkyl, and—CON(C₁₋₆alkyl)₂), and

the R⁵ phenyl ring is additionally optionally substituted with one ortwosubstituents independently selected from —C₁₋₆alkyl, -C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy.

Embodiment 6

In embodiment 6, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is phenylC₁₋₆alkyl, preferablybenzyl, wherein phenyl ring in phenylC₁₋₆alkyl and benzyl is substitutedat the meta or para position, preferably para, to the carbon atom of thephenyl ring that is attached to —C₁₋₆alkyl in —C₁₋₆alkylphenyl and —CH₂—in benzyl respectively, with phenyl, benzyl, benzyloxy, or phenoxy[wherein the phenyl ring either by itself or as part of benzyl,benzyloxy, and phenoxy is optionally substituted with one, two, or threesubstituents independently selected from hydroxy, halo, CN, —CO₂H,—COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl (substituted with oneto five fluoro), —OC₁₋₆alkyl (substituted with one to five fluoro),—C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl, tetrazolyl,—SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂,—CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂]; and

R⁵ phenyl is further optionally substituted with one or twosubstituentsindependently selected from —C₁₋₆alkyl, —C₁₋₆alkyl (wherein alkyl issubstituted with one to five fluoro), —O—C₁₋₆alkyl, —OC₁₋₆alkyl (whereinalkyl is substituted with one to five fluoro), halo, CN, —NH₂, andhydroxy.

Embodiment 7

In embodiment 7, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl, —CH₂-naphthyl,—(CH₂)₂-phenyl, or —(CH₂)₂-naphthyl, preferably —CH₂-phenyl, wherein thephenyl and naphthyl rings are optionally substituted with one, two, orthree substituents independently selected from methyl, ethyl, methoxy,ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy,trifluoromethoxy, —CH₂CO₂H, —CH₂CH₂CO₂H, —OCH₂CO₂H, —OCH₂CH₂CO₂H,—CH₂CO₂CH₃, —CH₂CH₂CO₂CH₃, —CH₂CO₂ethyl, —CH₂CH₂CO₂ethyl, —CH₂OH,—CH₂CH₂OH, —OCH₂OCH₃, —OCH₂CH₂OCH₃, —CO₂H, —COOmethyl, —CO₂ethyl,hydroxy, nitro, PO₃H₂, methylthio, ethylthio, methylsulfoxide,ethylsulfoxide, methylcarbonylaminosulfonyl, ethylcarbonylaminosulfonyl,fluoro, chloro, cyano, —NH₂, —NHCH₃, —NHethyl, —N(methyl)₂, —N(ethyl)₂,—CONR^(e)R^(f) (where R^(e) is hydrogen, methyl, ethyl, or propyl andR^(f) is hydrogen, methyl, ethyl, propyl, —(CH₂)₂—CO₂H, —(CH₂)₃—CO₂H,—(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me, —(CH₂)₂—CO₂ethyl, —(CH₂)₃—CO₂ethyl,—(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —(CH₂)₂—NHMe, —(CH₂)₃—NHMe, —(CH₂)₂—N(CH₃)₂,or —(CH₂)₃—N(CH₃)₂), —SO₂Me, —SO₂NR^(g)R^(h) (where R^(g) is hydrogen,methyl, ethyl, or propyl and R^(h) is hydrogen, methyl, ethyl, propyl,—(CH₂)₂—CO₂H, —(CH₂)₃—CO₂H, —(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me,—(CH₂)₂—CO₂ethyl, or —(CH₂)₃—CO₂ethyl), phenyl, phenoxy, —CH₂-phenyl,—CH₂—CH₂-phenyl, —OCH₂-phenyl or —OCH₂—CH₂-phenyl [wherein the phenylring, by itself or as part of phenoxy, —CH₂-phenyl, —CH₂—CH₂-phenyl,—OCH₂-phenyl, and —OCH₂—CH₂-phenyl, is optionally substituted with one,two, or three substituents independently selected from hydroxyl, chloro,fluoro, —CO₂H, CN, —CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl,—CH₂—CO₂H, —CH₂—CO₂methyl, —CH₂—CO₂ethyl, tetrazolyl, —SO₂CH₃, —SO₂NH₂,—SO₂NHCH₃, —SO₂N(CH₃)₂, —CONH₂, —CONHCH₃, and —CON(CH₃)21, 5- or6-membered monocyclic heteroaryl containing one to four heteroatomsindependently selected from O, N, and S [wherein the heteroaryl ring isoptionally substituted with one, two, or three substituentsindependently selected from from hydroxyl, chloro, fluoro, CN, —CO₂H,—CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, difluoromethyl, trifluoromethyl, —CH₂—CO₂H,—CH₂—CO₂methyl, and —CH₂—CO₂ethyl], —SR^(i), —OCH₂R^(i), —O(CH₂)₂—R^(i),—CH₂R^(i) and —(CH₂)2-R′ [where each R′ is independently 5- or6-membered monocyclic heteroaryl containing one to four heteroatomsindependently selected from O, N, and S and wherein the heteroaryl ringis optionally substituted with one, two, or three substituentsindependently selected from from hydroxyl, chloro, fluoro, CN, —CO₂H,—CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, difluoromethyl, trifluoromethyl, —CH₂—CO₂H,—CH₂—CO₂methyl, —CH₂—CO₂ethyl, tetrazolyl, —SO₂CH₃, —SO₂NH₂, —SO₂NHCH₃,—SO₂N(CH₃)₂, —CONH₂, —CONHCH₃, and —CON(CH₃)₂].

Embodiment 8

In embodiment 8, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl, —CH₂-naphthyl,—(CH₂)₂-phenyl, or —(CH₂)₂-naphthyl, preferably —CH₂-phenyl, whereinphenyl and naphthyl rings are substituted with one or two substituentsindependently selected from difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, —CH₂CO₂H, —CH₂CH₂CO₂H, —OCH₂CO₂H,—OCH₂CH₂CO₂H, —CH₂CO₂CH₃, —CH₂CH₂CO₂CH₃, —CH₂CO₂ethyl, —CH₂CH₂CO₂ethyl,—CH₂OH, —CH₂CH₂OH, —OCH₂OCH₃, —OCH₂CH₂OCH₃, —CO₂H, —COOmethyl,—CO₂ethyl, hydroxy, nitro, PO₃H₂, methylthio, ethylthio,methylsulfoxide, ethylsulfoxide, methylcarbonylaminosulfonyl,ethylcarbonylaminosulfonyl, fluoro, chloro, cyano, —NH₂, —NHCH₃,—NHethyl, —N(methyl)₂, —N(ethyl)₂, —CONR^(e)R^(f) (where R^(e) ishydrogen, methyl, ethyl, or propyl and R^(f) is hydrogen, methyl, ethyl,propyl, —(CH₂)₂—CO₂H, —(CH₂)₃—CO₂H, —(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me,—(CH₂)₂—CO₂ethyl, —(CH₂)₃—CO₂ethyl, —(CH₂)₂—NH₂, —(CH₂)₃—NH₂,—(CH₂)₂—NHMe, —(CH₂)₃—NHMe, —(CH₂)₂—N(CH₃)₂, or —(CH₂)₃—N(CH₃)₂),—SO₂Me, —SO₂NR^(g)R^(h) (where R^(g) is hydrogen, methyl, ethyl, orpropyl and R^(h) is hydrogen, methyl, ethyl, propyl, —(CH₂)₂—CO₂H,—(CH₂)3—CO₂H, —(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me, —(CH₂)₂—CO₂ethyl, or—(CH₂)₃—CO₂ethyl), phenyl, phenoxy, —CH₂-phenyl, —CH₂—CH₂-phenyl,—OCH₂-phenyl or —OCH₂—CH₂-phenyl [wherein the phenyl ring by itself oras part of phenoxy, —CH₂-phenyl, —CH₂—CH₂-phenyl, —OCH₂-phenyl, and—OCH₂—CH₂-phenyl is optionally substituted with one, two, or threesubstituents independently selected from hydroxyl, chloro, fluoro,—CO₂H, CN, —CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl,—CH₂—CO₂H, —CH₂—CO₂methyl, —CH₂—CO₂ethyl, tetrazolyl, —SO₂CH₃, —SO₂NH₂,—SO₂NHCH₃, —SO₂N(CH₃)₂, —CONH₂, —CONHCH₃, and —CON(CH₃)₂], 5- or6-membered monocyclic heteroaryl containing one to four heteroatomsindependently selected from O, N, and S [wherein the heteroaryl ring isoptionally substituted with one, two, or three substituentsindependently selected from from hydroxyl, chloro, fluoro, CN, —CO₂H,—CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, difluoromethyl, trifluoromethyl, —CH₂—CO₂H,—CH₂—CO₂methyl, —CH₂—CO₂ethyl, tetrazolyl, —SO₂CH₃, —SO₂NH₂, —SO₂NHCH₃,—SO₂N(CH₃)₂, —CONH₂, —CONHCH₃, and —CON(CH₃)₂], —OR^(i), —SR^(i),—OCH₂R^(i), —O(CH₂)₂—R^(i), —CH₂R^(i) and —(CH₂)₂—R^(i) [where eachR^(i) is independently 5- or 6-membered monocyclic heteroaryl containingone to four heteroatoms independently selected from O, N, and S andwherein the heteroaryl ring is optionally substituted with one, two, orthree substituents independently selected from from hydroxyl, chloro,fluoro, CN, —CO₂H, —CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl,—CH₂—CO₂H, —CH₂—CO₂methyl, and —CH₂—CO₂ethyl]; and the R⁵ phenyl andnaphthyl rings are additionally optionally substituted with a thirdsubstituent independently selected from methyl, ethyl, fluoro, chloro,methoxy, ethoxy, hydroxy, —NH₂, and cyano.

Embodiment 9

In embodiment 9, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein phenyl is substituted with onesubstituent at a meta or para position, preferably para, to the carbonatom of the phenyl ring that is attached to —CH₂— or —(CH₂)₂— in—CH₂-phenyl or —(CH₂)₂-phenyl respectively, and is selected fromtrifluoromethyl, difluoromethoxy, trifluoromethoxy, —CH₂CO₂H,—CH₂CH₂CO₂H, —OCH₂CO₂H, —OCH₂CH₂CO₂H, —CH₂CO₂CH₃, —CH₂CH₂CO₂CH₃,—CH₂CO₂ethyl, —CH₂CH₂CO₂ethyl, —CH₂OH, —CH₂CH₂OH, —OCH₂CH₂OH, —OCH₂OCH₃,—OCH₂CH₂OCH₃, —CO₂H, —COOmethyl, —COOethyl, hydroxy, fluoro, chloro,cyano, —CONR^(e)R^(f) (where R^(e) is hydrogen, methyl, ethyl, or propyland R^(f) is hydrogen, methyl, ethyl, propyl, —(CH₂)₂—CO₂H,—(CH₂)₃—CO₂H, —(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me, —(CH₂)₂—CO₂ethyl,—(CH₂)₃—CO₂ethyl, —(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —(CH₂)₂—NHMe, —(CH₂)₃—NHMe,—(CH₂)₂—NHCH₃, —(CH₂)₃—N(CH₃)₂), —SO₂Me, or —SO₂NR^(g)R^(h) (where R^(g)is hydrogen, methyl, ethyl, or propyl and R^(h) is hydrogen, methyl,ethyl, propyl, —(CH₂)₂—CO₂H, —(CH₂)₃—CO₂H, —(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me,—(CH₂)₂—CO₂ethyl, or —(CH₂)₃—CO₂ethyl), tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl,thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl orisoxazolyl, wherein each of the aforementioned heteroaryl rings isoptionally substituted with one or two substituents independentlyselected from C₁₋₆alkyl, halo, CN, —CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to five fluoro, or—OC₁₋₆alkyl (substituted with one to five fluoro); and

the R⁵ phenyl ring is additionally optionally substituted with one ortwo substituents independently selected from methyl, ethyl, fluoro,chloro, methoxy, ethoxy, hydroxy, —NH₂, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, and cyano.

Embodiment 10

In embodiment 10, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein the phenyl ring in —CH₂-phenyl and—(CH₂)₂-phenyl is substituted at the meta or para position to the carbonatom of the phenyl ring that is attached to the —CH₂— group of the—CH₂-phenyl and —(CH₂)₂-phenyl ring with haloC₁₋₆alkoxy or haloC₁₋₆alkyland the R⁵ phenyl ring is additionally optionally substituted with oneor two substituents independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy.

Embodiment 11

In embodiment 11, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein phenyl is substituted with a substituentat the meta or para position, preferably para position, to the carbonatom of the phenyl ring that is attached to —CH₂— or —(CH₂)₂— in—CH₂-phenyl or —(CH₂)₂-phenyl, which substituent is selected from—CONR^(e)R^(f) (where R^(e) is hydrogen or —C₁₋₆alkyl and R^(f) is—C₁₋₆alkylene-substituted with one or two substituents independentlyselected from hydroxyl, NH₂, —NHC₁₋₆alkyl or —N(C₁₋₆alkyl)₂), —OR^(i),—C₁₋₆alkylene-R^(i), —OC₁₋₆alkylene-R^(i), —SR^(i),—SC₁₋₆alkylene-R^(i), —CONR^(m)R^(i), —CONR^(m)C₁₋₆alkylene-R^(i) [whereeach R^(i) is independently 5- or 6-membered monocyclic heteroarylcontaining one to four heteroatoms independently selected from O, N, andS and wherein the heteroaryl ring is optionally substituted with one,two, or three substituents independently selected from hydroxyl, halo,CN, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl (wherein alkyl issubstituted with one to five fluoro), or —OC₁₋₆alkyl (wherein alkyl issubstituted with one to five fluoro), heterocyclyl,—C₁₋₆alkyleneheterocyclyl, —OC₁₋₆alkyleneheterocyclyl,—SC₁₋₆alkyleneheterocyclyl, —CONR^(m)C₁₋₆alkyleneheterocyclyl,—NR^(m)COheterocyclyl, —COheterocyclyl,—NR^(m)COC₁₋₆alkyleneheterocyclyl [wherein each R^(m) is hydrogen or—C₁₋₆alkyl and the heterocyclyl ring by itself or as part of—C₁₋₆alkyleneheterocyclyl, —OC₁₋₆alkyleneheterocyclyl,—SC₁₋₆alkyleneheterocyclyl, —CONR^(m)C₁₋₆alkyleneheterocyclyl,—COheterocyclyl, —NR^(m)COheterocyclyl, and—NR^(m)COC₁₋₆alkyleneheterocyclyl is optionally substituted with one,two, or three substituents independently selected from hydroxy, halo,—COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, or —C₁₋₆alkyl (wherein alkyl issubstituted with hydroxy or —OC₁₋₆alkyl)], and—NR^(m)COC₁₋₆alkyleneNR^(o)R^(p) (where R^(m), R^(o) and R^(p) areindependently hydrogen or C₁₋₆alkyl); and

the R⁵ phenyl ring is additionally optionally substituted with one ortwo substituents independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy.

Embodiment 12

In embodiment 12, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein phenyl is substituted with —CH═CHCO₂H,—CH₂CO₂H or CH₂CH₂CO₂ at the meta or para position, preferably para, tothe carbon atom of the phenyl ring that is attached to —CH₂— or —(CH₂)₂—in —CH₂-phenyl or —(CH₂)₂-phenyl; and the phenyl ring is additionallyoptionally substituted with one or two substituents independentlyselected from —C₁₋₆alkyl, —C₁₋₆alkyl (wherein alkyl is substituted withone to five fluoro), —O—C₁₋₆alkyl, —OC₁₋₆alkyl (wherein alkyl issubstituted with one to five fluoro), halo, CN, —NH₂, and hydroxy.

Embodiment 13

In embodiment 13, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein phenyl is substituted —CH₂CO₂CH₃,—CH₂CH₂CO₂CH₃, —CH₂CO₂ethyl, or —CH₂CH₂CO₂ethyl at the meta or paraposition, preferably para, to the carbon atom of the phenyl ring that isattached to —CH₂— or —(CH₂)₂— in —CH₂-phenyl or —(CH₂)₂-phenyl; and theR⁵ phenyl ring is additionally optionally substituted with one or twosubstituents independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl (whereinalkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl, —OC₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), halo, CN, —NH₂,and hydroxy.

Embodiment 14

In embodiment 14, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl (benzyl), wherein phenyl is substituted with CO₂Hat the meta or para position, preferably para, to the carbon atom of thephenyl ring that is attached to —CH₂— or —(CH₂)₂— in —CH₂-phenyl(benzyl) or —(CH₂)₂-phenyl and the R⁵ phenyl ring is additionallyoptionally substituted with one or two substituents independentlyselected from —C₁₋₆alkyl, —C₁₋₆alkyl (wherein alkyl is substituted withone to five fluoro), —O—C₁₋₆alkyl, —OC₁₋₆alkyl (wherein alkyl issubstituted with one to five fluoro), halo, CN, —NH₂, and hydroxy.

Embodiment 15

In embodiment 15, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl (benzyl) or—(CH₂)₂-phenyl, preferably —CH₂-phenyl (benzyl), wherein phenyl issubstituted with —COOmethyl or —COOethyl at the meta or para position,preferably para, to the carbon atom of the phenyl ring that is attachedto —CH₂— or —(CH₂)₂— in —CH₂-phenyl (benzyl) or —(CH₂)₂-phenyl and theR⁵ phenyl ring is additionally optionally substituted with one or twosubstituents independently selected from from —C₁₋₆alkyl, —C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy .

Embodiment 16

In embodiment 16, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein phenyl is substituted with fluoro,chloro, or cyano at the meta or para position, preferably para, to thecarbon atom of the phenyl ring that is attached to —CH₂— or —(CH₂)₂— in—CH₂-phenyl or —(CH₂)₂-phenyl and the R⁵ phenyl ring is additionallyoptionally substituted with one or two substituents independentlyselected from —C₁₋₆alkyl, —C₁₋₆alkyl (wherein alkyl is substituted withone to five fluoro), —O—C₁₋₆alkyl, —OC₁₋₆alkyl (wherein alkyl issubstituted with one to five fluoro), halo, CN, —NH₂, and hydroxy

Embodiment 17

In embodiment 17, the compounds of embodiment 1or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein phenyl is substituted with—CONR^(e)R^(f) (where R^(e) is hydrogen, methyl, ethyl, or propyl andR^(f) is hydrogen, methyl, ethyl, propyl, —(CH₂)₂—CO₂H, —(CH₂)₃—CO₂H,—(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me, —(CH₂)₂—CO₂ethyl, —(CH₂)₃—CO₂ethyl,—(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —(CH₂)₂—NHMe, —(CH₂)₃—NHMe, —(CH₂)₂—NHCH₃,—(CH₂)₃—N(CH₃)₂) or —CONHSO₂R^(z) where R^(z) is —C₁₋₆alkyl,—NHC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ at the meta or para position, preferablypara, to the carbon atom of the phenyl ring that is attached to —CH₂— or—(CH₂)₂— in —CH₂-phenyl or —(CH₂)₂-phenyl; and

the R⁵ phenyl ring is additionally optionally substituted with one ortwo substituents independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy.

Embodiment 18

In embodiment 18, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein phenyl is substituted —SO₂NR^(g)R^(h)(where R^(g) is hydrogen, methyl, ethyl, or propyl and R^(h) ishydrogen, methyl, ethyl, propyl, —(CH₂)₂—CO₂H, —(CH₂)₃—CO₂H,—(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me, —(CH₂)₂—CO₂ethyl, or —(CH₂)₃—CO₂ethyl) or—SO₂NHCOR^(j) (where R^(j) is —C₁₋₆alkyl, —NHC₁₋₆alkyl, or—N(C₁₋₆alkyl)₂) at the meta or para position, preferably para, to thecarbon atom of the phenyl ring that is attached to —CH₂— or —(CH₂)₂— in—CH₂-phenyl or —(CH₂)₂-phenyl; and

the R⁵ phenyl ring is additionally optionally substituted with one ortwo substituents independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy.

Embodiment 19

In embodiment 19, the compounds of embodiment 1 or 2 and subembodimentscontained therein are those wherein R⁵ is —CH₂-phenyl or —(CH₂)₂-phenyl,preferably —CH₂-phenyl, wherein phenyl is substituted with tetrazol-5-ylat the meta or para position, preferably para, to the carbon atom of thephenyl ring that is attached to —CH₂— or —(CH₂)₂— in —CH₂-phenyl or—(CH₂)₂-phenyl; and

the R⁵ phenyl ring is additionally optionally substituted with one ortwo substituents independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy.

Embodiment 20

In embodiment 20, the compounds of embodiment 1 and subembodimentscontained therein are those wherein R⁵ is 5-10 memberedheteroarylC₁₋₆alkyl (also referred to below as R⁵ heteroaryl),preferably —CH₂— or —(CH₂)₂-5-10 membered heteroaryl, having one tothree heteroatoms independently selected from N, O, or S and isoptionally substituted, preferably substituted, with one or twosubstituents, more preferably one substituent, independently selectedfrom —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to fivefluoro, —OC₁₋₆alkyl substituted with one to five fluoro,—C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl, —C₂₋₆alkenylene-CO₂H,—C₁₋₆alkyl substituted with one or two substituents independentlyselected from hydroxy, —OC₁₋₆alkyl substituted with hydroxy, —C₁₋₆alkylsubstituted with one or two —OC₁₋₆alkyl, —OC₁₋₆alkyl (substituted withone or two —OC₁₋₆alkyl), —CO₂H, —COOC₁₋₆alkyl, hydroxy, halo, nitro,—PO₃H₂, cyano, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —CONR^(e)R^(f)(where R^(e) and R^(f) are independently hydrogen, —C₁₋₆alkyl,—C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl, or —C₁₋₆alkylsubstituted with one or two substituents independently selected fromhydroxyl, —NHC₁₋₆alkyl or —N(C₁₋₆alkyl)₂), —SO₂(C₁₋₆alkyl),—SO₂NR^(g)R^(h) (where R^(g) and R^(h) are independently hydrogen,—C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H, or —C₁₋₆alkylene-CO₂C₁₋₆alkyl),—SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂NHCOR^(j) (where R^(j) is —C₁₋₆alkyl,—NH₂, —NHC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂), phenyl, —C₁₋₆alkylenephenyl,phenoxy, —OC₁₋₆alkylenephenyl, 5- or 6-membered monocyclic heteroarylcontaining one to four heteroatoms independently selected from O, N, andS [wherein the heteroaryl ring is optionally substituted with one, two,or three substituents independently selected from hydroxyl, halo, CN,—CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl (substitutedwith one to five fluoro), —OC₁₋₆alkyl (substituted with one to fivefluoro), —C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl, tetrazolyl,—SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂N(C₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂,—CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂], —OR^(i), —C₁₋₆alkylene-R^(i),—OC₁₋₆alkylene-R^(i), —SR^(i), —SC₁₋₆alkylene-R^(i), heterocyclyl,—C₁₋₆alkyleneheterocyclyl, —OC₁₋₆alkyleneheterocyclyl,—SC₁₋₆alkyleneheterocyclyl, —CONR^(m)C₁₋₆alkyleneheterocyclyl,—NR^(m)COC₁₋₆alkyleneNR^(o)R^(p), —NR^(m)COheterocyclyl,—NR^(m)COC₁₋₆alkyleneheterocyclyl, —COheterocyclyl, —CONR^(m)R^(i),—CONR^(m)alkylene-R^(i), —OCONR^(m)R^(m), —NR^(m)—COR^(y),—NR^(m)—CO—NR^(m)R^(y), —NR^(m)—SO₂—R^(y), —NR^(m)—SO₂—NR^(m)R^(y), and—CONHSO₂R^(z); and

the R⁵ heteroaryl ring is additionally optionally substituted with anadditional substituent selected from —C₁₋₆alkyl, —C₁₋₆alkyl (whereinalkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl, —OC₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), halo, CN, —NH₂,and hydroxy; wherein:

each R^(m) is hydrogen or —C₁₋₆alkyl;

R^(o), R^(p), and R^(y) are independently hydrogen or —C₁₋₆alkyl;

R^(z) is —C₁₋₆alkyl, —NHC₁₋₆alkyl, or —N(C₁₋₆alkyl)₂, phenyl by itselfor as part of —C₁₋₆alkylenephenyl, phenoxy, or —OC₁₋₆alkylenephenyl isoptionally substituted with one, two, or three substituentsindependently selected from hydroxyl, halo, CN, —CO₂H, —COOC₁₋₆alkyl,—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to five fluoro,—OC₁₋₆alkyl (substituted with one to five fluoro), —C₁₋₆alkylene-CO₂H,—C₁₋₆alkylene-CO₂C₁₋₆alkyl, tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂,—SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂, —CONHC₁₋₆alkyl, and—CON(C₁₋₆alkyl)₂;

each R^(i) is independently 5- or 6-membered monocyclic heteroarylcontaining one to four heteroatoms independently selected from O, N, andS and wherein the heteroaryl ring is optionally substituted with one,two, or three substituents independently selected from hydroxyl, halo,CN, —CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkylsubstituted with one to five fluoro, —OC₁₋₆alkyl (substituted with oneto five fluoro), —C₁₋₆alkylene-CO₂H, and —C₁₋₆alkylene-CO₂C₁₋₆alkyl,tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂,—CONH₂, —CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂;

heterocyclyl by itself or as part of —C₁₋₆alkyleneheterocyclyl,—OC₁₋₆alkyleneheterocyclyl, —SC₁₋₆alkyleneheterocyclyl,—CONR^(m)C₁₋₆alkyleneheterocyclyl, —NR^(m)COheterocyclyl,—COheterocyclyl, and —NR^(m)COC₁₋₆alkyleneheterocyclyl is optionallysubstituted with one, two, or three substituents independently selectedfrom hydroxy, halo, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, or—C₁₋₆alkyl (substituted with hydroxy or —OC₁₋₆alkyl).

Embodiment 21

In embodiment 21, the compounds of embodiment 1 or 20 and subembodimentscontained therein are those wherein R⁵ is —CH₂— or —(CH₂)₂-(5-9 memberedheteroaryl ring) which heteroaryl ring is optionally substituted withone or two substituents, preferably one substituent, independentlyselected from difluoromethyl, trifluoromethyl, difluoromethoxy,trifluoromethoxy, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CO₂CH₃, —CH₂CH₂CO₂CH₃,—CH₂CO₂ethyl, —CH₂CH₂CO₂ethyl, —CH₂OH, —CH₂CH₂OH, —OCH₂CH₂OH, —OCH₂OCH₃,—OCH₂CH₂OCH₃, —CO₂H, —COOmethyl, —CO₂ethyl, hydroxy, nitro, PO₃H₂,methylthio, ethylthio, methylsulfoxide, ethylsulfoxide,methylcarbonylaminosulfonyl, ethylcarbonylaminosulfonyl, fluoro, chloro,cyano, —NH₂, —NHCH₃, —NHethyl, —N(methyl)₂, —N(ethyl)₂, —CONR^(e)R^(f)(where R^(e) is hydrogen, methyl, ethyl, or propyl and R^(f) ishydrogen, methyl, ethyl, propyl, —(CH₂)₂—CO₂H, —(CH₂)₃—CO₂H,—(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me, —(CH₂)₂—CO2ethyl, —(CH₂)₃—CO₂ethyl,—(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —(CH₂)₂—NHMe, —(CH₂)₃—NHMe, —(CH₂)₂—N(CH₃)₂,or —(CH₂)₃—N(CH₃)₂), -S02Me, —SO₂NR^(g)R^(h) (where R^(g) is hydrogen,methyl, ethyl, or propyl and R^(h) is hydrogen, methyl, ethyl, propyl,—(CH₂)₂—CO₂H, —(CH₂)₃—CO₂H, —(CH₂)₂—CO₂Me, —(CH₂)₃—CO₂Me,—(CH₂)₂—CO₂ethyl, or —(CH₂)₃—CO₂ethyl), phenyl, phenoxy, —CH₂-phenyl,—CH₂—CH₂-phenyl, —OCH₂-phenyl or —OCH₂—CH₂-phenyl [wherein the phenylring by itself or as part of phenoxy, —CH₂-phenyl, —CH₂—CH₂-phenyl,—OCH₂-phenyl, and —OCH₂—CH₂-phenyl is optionally substituted with one,two, or three substituents independently selected from hydroxyl, chloro,fluoro, —CO₂H, CN, —CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl,—CH₂—CO₂H, —CH₂—CO₂methyl, —CH₂—CO₂ethyl, tetrazolyl, —SO₂CH₃, —SO₂NH₂,—SO₂NHCH₃, —SO₂N(CH₃)₂, —CONH₂, —CONHCH₃, and —CON(CH₃)₂], 5- or6-membered monocyclic heteroaryl containing one to four heteroatomsindependently selected from O, N, and S [wherein the heteroaryl ring isoptionally substituted with one, two, or three substituentsindependently selected from from hydroxyl, chloro, fluoro, CN, —CO₂H,—CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, difluoromethyl, trifluoromethyl, —CH₂—CO₂H,—CH₂—CO₂methyl, —CH₂—CO₂ethyl, tetrazolyl, —SO₂CH₃, —SO₂NH₂, —SO₂NHCH₃,—SO₂N(CH₃)₂, —CONH₂, —CONHCH₃, and —CON(CH₃)₂], —OR^(i), —SR^(i),—OCH₂R^(i), —O(CH₂)₂—R^(i), —CH₂R^(i) and —(CH₂)₂—R^(i) [where eachR^(i), is independently 5- or 6-membered monocyclic heteroarylcontaining one to four heteroatoms independently selected from O, N, andS and wherein the heteroaryl ring is optionally substituted with one,two, or three substituents independently selected from from hydroxyl,chloro, fluoro, CN, —CO₂H, —CO₂Me, —CO₂ethyl, methyl, ethyl, methoxy,ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl,trifluoromethyl, —CH₂—CO₂H, —CH₂—CO₂methyl, and —CH₂—CO₂ethyl]; and

the R⁵ heteroaryl ring is optionally additionally substituted with asubstituent selected from methyl, ethyl, fluoro, chloro, methoxy,ethoxy, hydroxy, —NH₂, and cyano.

Embodiment 22

In embodiment 22, the compounds of embodiment 1 or 20 and subembodimentscontained therein are those wherein R⁵ is —(CH₂)₁₋₂-(5-10 memberedheteroaryl ring) having one to three heteroatoms independently selectedfrom N, O, or S, preferably —CH₂-(5-9 membered heteroaryl ring) havingone to 3 heteroatoms independently selected from N, O, or S, wherein theheteroaryl ring is substituted with one or two substituentsindependently selected from —OC₁₋₆alkyl, —C₁₋₆alkyl substituted with oneto five fluoro, —OC₁₋₆alkyl (wherein alkyl is substituted with one tofive fluoro), —C₁₋₆alkylene-CO₂H, —C₁₋₆alkylene-CO₂C₁₋₆alkyl, —CO₂H,nitro, —COOC₁₋₆alkyl, halo, hydroxy, cyano, —CONR^(e)R^(f) (where R^(e)is hydrogen or —C₁₋₆alkyl and R^(f) is —C₁₋₆alkyl, —C₁₋₆alkylene-CO₂H,or —C₁₋₆alkylene-CO₂C₁₋₆alkyl), —SO₂(C₁₋₆alkyl), —SO₂NR^(g)R^(h) (whereR^(g) is hydrogen or —C₁₋₆alkyl and R^(h) is hydrogen, —C₁₋₆alkyl,—C₁₋₆alkylene-CO₂H, or —C₁₋₆alkylene-CO₂C₁₋₆alkyl), tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl,oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl,pyrrolyl or isoxazolyl, (wherein each of the aforementioned heteroarylrings is optionally substituted with one or two substituentsindependently selected from C₁₋₆alkyl, halo, CN, —CO₂H, —COOC₁₋₆alkyl,—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl substituted with one to five fluoro,—OC₁₋₆alkyl (substituted with one to five fluoro, tetrazolyl,—SO₂C₁₋₆alkyl, —SO₂NH₂, —SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂,—CONHC₁₋₆alkyl, and —CON(C₁₋₆alkyl)₂); and

the R⁵ heteroaryl ring is additionally optionally substituted with oneor two substituents, independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl,—OC₁₋₆alkyl (wherein alkyl is substituted with one to five fluoro),halo, CN, —NH₂, and hydroxy.

Embodiment 23

In embodiment 23, the compounds of embodiment 1 or 20 and subembodimentscontained therein are those wherein R⁵ is 5-10 memberedheteroarylC₁₋₆alkyl having one to 3 heteroatoms independently selectedfrom N, O, or S wherein the heteroaryl ring is substituted with phenyl[wherein the phenyl ring is optionally substituted with one, two, orthree substituents independently selected from hydroxyl, halo, CN,—CO₂H, —COOC₁₋₆alkyl, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl (wherein alkylis substituted with one to five fluoro), —OC₁₋₆alkyl (wherein alkyl issubstituted with one to five fluoro), —C₁₋₆alkylene-CO₂H,—C₁₋₆alkylene-CO₂C₁₋₆alkyl, tetrazolyl, —SO₂C₁₋₆alkyl, —SO₂NH₂,—SO₂NHC₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —CONH₂, —CONHC₁₋₆alkyl, and—CON(C₁₋₆alkyl)₂]; and

the R⁵ heteroaryl ring is further optionally substituted with twosubstituents independently selected from —C₁₋₆alkyl, —C₁₋₆alkyl (whereinalkyl is substituted with one to five fluoro), —O—C₁₋₆alkyl, —OC₁₋₆alkyl(wherein alkyl is substituted with one to five fluoro), halo, CN, —NH₂,and hydroxy.

Embodiment 24

In embodiment 24, the compounds of embodiment 1, 20, 21, 22, or 23 andsubembodiments contained therein are those wherein the heteroaryl ringin the —CH₂-(5-10 membered heteroaryl ring) of R⁵ is selected fromthienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl, oxazolyl, oxadiazolyl, isoxazolyl,thiazolyl, thiadiazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl,indolyl, and benzothienyl. In one subembodiment of embodiment 24, theheteroaryl ring is a 9- or 10-membered heteroaryl ring selected frombenzimidazol-5-yl, benzoxazol-5-yl, indol-5-yl, benzimidazol-2-yl,benzoxazol-2-yl, benzofuran-5-yl, indol-2-yl, quinolinyl, orisoquinolinyl. In one subembodiment of embodiment 24, the heteroarylring is 5-membered heteroaryl ring that is preferably substituted at the3-position to the ring atom of the 5-membered ring that is attached to—CH₂—, and the 6-membered heteroaryl ring is substituted at a meta orpara position to the ring atom that is attached to the —CH₂— andfurthermore, the above rings are optionally substituted, preferablysubstituted, with one or more substituent(s) as indicated in embodiments20, 21, 22, or 23 above.

Embodiment 25

In embodiment 25, the compounds of any one of embodiments 1-24 andsubembodiments contained therein are those wherein R³ is hydrogen, X is0, and Y is 0.

Embodiment 26

In embodiment 26, the compounds of any one of embodiments 1-24 andsubembodiments contained therein are those are wherein R³ is hydrogen,C₁₋₆alkyl, or benzyl, X is CH₂, and Y is O. In one group of compoundswithin embodiment 26, R³ is hydrogen, X is CH₂, and Y is O.

Embodiment 27

In embodiment 27, the compounds of any one of embodiments 1-24 andsubembodiments contained therein are those wherein R³ is hydrogen, X isN. Within embodiment 27, in one group of compounds Y is O. Withinembodiment 27, in another group of compounds Y is S.

Embodiment 28

In embodiment 28, the compounds of any one of embodiments 1-24 andsubembodiments contained therein are those wherein R³ is hydrogen, X isO, and Y is S.

Embodiment 29

In embodiment 29, the compounds of any one of embodiments 1-24 andsubembodiments contained therein and groups contained therein are thosewherein R³ is hydrogen, X is CH₂, and Y is S.

Embodiment 30

In embodiment 30, the compounds of any one of embodiments 1-29 andsubembodiments contained therein and groups contained therein are thosewherein:

R^(1a) is hydroxy, halo, C₁₋₆alkyl, cyano, azido, NH₂,C₁₋₆alkylcarbonyloxy, ethynyl, or vinyl; preferably hydroxy, fluoro,chloro, cyano, azido, NH₂, or methyl;

R^(1b) is hydrogen;

R^(2a) is hydrogen, hydroxy, halo, C₁₋₆alkyl, NH₂, cyano, azido,ethynyl, or vinyl; and

R^(2b) is hydrogen.

Embodiment 31

In embodiment 31, the compounds of embodiment 30 are those wherein:

R^(1a) is hydroxy, fluoro, or methyl;

R^(1b) is hydrogen;

R^(2a) is hydroxy, fluoro, or methyl; and

R^(2b) is hydrogen.

Embodiment 32

In embodiment 32, the compounds of embodiment 30 are those wherein:

R^(1a) is fluoro;

R^(1b) is hydrogen;

R^(2a) is hydroxy, hydrogen, methyl or NH₂; and

R^(2b) is hydrogen.

Within embodiment 32, in one group of compounds R^(2a) is hydrogen.

Within embodiment 32, in another group of compounds R^(2a) is hydroxy.

Within embodiment 32, in yet another group of compounds R^(2a) ismethyl.

Within embodiment 32, in yet another group of compounds R^(2a) is NH₂.

Embodiment 33

In embodiment 33, the compounds of embodiment 30, 31 and 32 and groupscontained therein are those wherein:

Embodiment 34

In embodiment 34, the compounds of embodiment 30, 31 and 32 and groupscontained therein are those wherein:

Embodiment 35

In embodiment 35, the compounds of embodiment 30, 31 and 32 and groupscontained therein are those wherein:

Embodiment 36

In embodiment 36, the compounds of embodiment 30, 31 and 32 and groupscontained therein are those wherein:

Embodiment 37

In embodiment 37, the compounds of embodiment 30, 31 and 32 and groupscontained therein are those wherein:

Embodiment 38

In embodiment 38, the compounds of embodiment 30, 31 and 32 and groupscontained therein are those wherein:

Embodiment 39

In embodiment 39, the compounds of any one of embodiments 1-29 are thosewherein:

R^(1a) is halo, C₁₋₆alkyl, cyano, azido, NH₂, C₁₋₆alkylcarbonyloxy,ethynyl, or vinyl;

R^(1b) is hydroxy or fluoro;

R²ais hydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, NH₂, ethynyl, orvinyl; and

R^(2b) is hydrogen.

Embodiment 40

In embodiment 40, the compounds of embodiment 39 are those wherein:

R^(1a) is fluoro or methyl;

R^(1b) is fluoro or hydroxy;

R^(2a) is hydrogen, hydroxy, NH₂, methyl, methoxy, ethoxy, or propoxy;and

R^(2b) is hydrogen.

Embodiment 41

In embodiment 41, the compounds of embodiments any one of embodiments1-29 are those wherein:

R^(1a) is hydroxy, halo, C₁₋₆alkyl, or cyano;

R^(1b) is hydrogen;

R²ais hydroxy, halo, C₁₋₆alkyl, cyano, ethynyl, or vinyl; and

R^(2b) is halo, hydroxy, or C₁₋₆alkyl.

Embodiment 42

In embodiment 42, the compound of embodiment 42 are those wherein:

R^(1a) is hydroxy, fluoro, or methyl;

R^(1b) is hydrogen;

R^(2a) is methyl, fluoro, cyano, or hydroxy; and

R^(2b) is fluoro, hydroxyl, or methyl.

Embodiment 43

In embodiment 43, the compound of embodiment 42 are those wherein:

R^(1a) is fluoro or methyl;

R^(1b) is hydrogen;

R^(2a) is methyl; and

R^(2b) is fluoro, hydroxy, or methyl.

Embodiment 44

In embodiment 44, the compound of any one of embodiments 1-29 andsubembodiments and groups of compounds contained therein are thosewherein:

R^(1a) is halo, C₁₋₆alkyl, cyano, azido, NH₂, C₁₋₆alkylcarbonyloxy,ethynyl, or vinyl;

R^(1b) is hydroxy or fluoro;

R^(2a) is hydroxy, halo, C₁₋₆alkyl, or cyano; and

R^(2b) is halo, hydroxy, or C₁₋₆alkyl.

Embodiment 45

In embodiment 45, the the compounds of any one of embodiments 1 to 45and subembodiments and groups of compounds contained therein are thosewherein:

R⁴ is selected from —C(O)OR⁹, —C(O)NR¹¹R¹², —S(O)₂R¹⁰,—P(O)(OR¹¹)(OR¹²), and —P(O)(OR¹¹)(NR¹³R¹⁵); and

R⁶ is selected from —C(O)OR^(S) and —P(O)(OR¹¹)(OR¹²); wherein: R⁹, R¹⁰,R¹¹, R¹², R¹³ and R¹⁵ are independently hydrogen or C₁₋₆ alkyl.

Within the groups of compounds in embodiment 46, in one group ofcompounds, R⁴ and R⁶ are —C(O)OR^(S) where R⁹ is as defined above,preferably R⁹ is hydrogen or C₁₋₆ alkyl.

Within the groups of compounds in embodiment 46, in another group ofcompounds, R⁴ and R⁶ are —C(O)OH.

Within the groups of compounds in embodiment 46, in yet another group ofcompounds, R⁴ is selected from —C(O)NR¹¹R¹² or —S(O)₂R¹¹; and

R⁶ is selected from —C(O)OR^(S) and —P(O)(OR¹¹)(OR¹²); wherein: R⁹, R¹¹,and R¹² are independently hydrogen or C₁₋₆ alkyl. In one subembodiment,the compounds are those wherein R⁹, R¹¹, and R¹² are independentlyhydrogen, methyl, or ethyl.

Within the groups of compounds in embodiment 46, in yet another group ofcompounds, R⁴is P(O)(OR¹¹)(OR¹²); and

R⁶ is —P(O)(OR¹¹)(OR¹²); wherein:

R¹¹ and R¹² are independently hydrogen or C₁₋₆ alkyl, preferably R¹¹ andR¹² are independently hydrogen, methyl, or ethyl.

Embodiment 46

In embodiment 46, the the compounds of embodiments 1 to 46 andsubembodiments and groups of compounds contained therein are thosewherein:

Het is a group selected from a group of formula (i) through (xiv) below:

wherein:

R^(u) is hydrogen, halo, cyano, —NH₂, —NHR²⁰, —NHCOR²⁰, —NR²⁰R²¹, —R²⁰,—SR²⁰, —OH, and —OR²⁰,

R^(w) is hydrogen, halo, —NHR²², —NR²²R²³, —R²², —OH, and —OR²²;

R^(v) and R^(x) are independently hydrogen, halo, haloC₁₋₆alkyl, —NH₂,—NHR²⁴, —NR²⁴R²⁵, —R²⁴, —SR²⁴, cyano, —OH, —SO₂R²⁴, —C₁₋₆alkyleneNH₂,—C₁₋₆alkyleneNHR²⁴, —C₁₋₆alkyleneNR²⁴R²⁵, —R²⁴, —C₁₋₆alkyleneSR²⁴,—C₁₋₆alkyleneOH, —C₁₋₆alkyleneOR²⁴, —C₁₋₆alkyleneSO₂R²⁴,

R^(s) and R^(t) are independently hydrogen, halo, or C₁₋₆alkyl; andwherein:

R²⁰, R²¹, R²², R²³, R²⁴ and R²⁵ are independently optionally substitutedC₁₋₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylC₁₋₆alkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl,optionally substituted aryl, optionally substituted arylC₁₋₆alkyl,optionally substituted heteroaryl, or optionally substitutedheteroarylC₁₋₆alkyl; or R²⁰ and R²¹, R²² and R²³, and R²⁴ and R²⁵together with the nitrogen to which they are attached form an optionallysubstituted nitrogen-containing heterocyclyl.

Embodiment 47

In embodiment 47, the compounds of embodiment 47 are those wherein Hetis a group of formula (i).

Embodiment 48

In embodiment 48, the compounds of embodiment 47 are those wherein Hetis a group of formula (ii).

Embodiment 49

In embodiment 49, the compounds of embodiment 47 are those wherein Hetis a group of formula (iii).

Embodiment 50

In embodiment 50, the compounds of embodiment 47 are those wherein Hetis a group of formula (iv).

Embodiment 51

In embodiment 51, the compounds of embodiment 47 are those wherein Hetis a group of formula (vi).

Embodiment 52

In embodiment 52, the compounds of embodiment 47 are those wherein Hetis a group of formula (vii).Embodiment 53:

In embodiment 53, the compounds of embodiment 47 are those wherein Hetis a group of formula (viii).

Embodiment 54

In embodiment 54, the compounds of any one of embodiments 47-54 andsubembodiments and groups of compounds contained therein are thosewherein R^(s) is hydrogen.

Embodiment 55

In embodiment 55, the compounds of any one of embodiments 47-55 andsubembodiments and groups of compounds contained therein are thosewherein R^(w) and R^(d) are hydrogen.

Embodiment 56

In embodiment 56, the compounds of any one of embodiments 47-56 andembodiments and groups of compounds contained therein are those wherein:

R^(u) is hydrogen, halo, cyano, —NH₂, —NHR²⁰, —NHCOR²⁰, —NR²⁰R²¹, —R²⁰,—SR²⁰, or —OR²⁰ wherein R²⁰ and R²¹ are independently optionallysubstituted C₁₋₆alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylC₁₋₆alkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylC₁₋₆alkyl, optionally substitutedaryl, optionally substituted arylC₁₋₆alkyl, optionally substitutedheteroaryl, or optionally substituted heteroarylC₁₋₆alkyl; or R²⁰ andR²¹ together with the nitrogen to which they are attached form anoptionally substituted nitrogen-containing heterocyclyl;

R^(v) is hydrogen, halo, haloC₁₋₆alkyl, cyano, —R²⁴, —SR²⁴, —OR²⁴, or—SO₂R²⁴; wherein:

R²⁴ is optionally substituted C₁₋₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylC₁₋₆alkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylC₁₋₆alkyl, optionally substituted aryl,optionally substituted arylC₁₋₆alkyl, optionally substituted heteroaryl,or optionally substituted heteroarylC₁₋₆alkyl.

Embodiment 57

In embodiment 57, the compounds of any one of embodiments 47-56 andsubembodiments and groups of compounds contained therein are thosewherein:

R^(u) is —NH₂, —NHR²⁰, or —NR²⁰R²¹ wherein R²⁰ and R²¹ are independentlyoptionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylC₁₋₆alkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl, optionallysubstituted aryl, optionally substituted arylC₁₋₆alkyl, optionallysubstituted heteroaryl, or optionally substituted heteroarylC₁₋₆alkyl;or R²⁰ and R²¹ together with the nitrogen to which they are attachedform an optionally substituted nitrogen-containing heterocyclyl;preferably —NH₂, and

R^(v) is halo, preferably chloro.

Representative compounds of Formula (I) include those in Table 1A:

TABLE 1A Cpd. # Compound Name  6

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2- benzylmalonic acid  7

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-(4-carboxybenzyl)-malonic acid  8

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((6- chloropyridin-3-yl)methyl)malonic acid 10

2-(((2R,3R,4R,5R)-5-(6-amino- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-benzylmalonic acid 12

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-(2-carboxyethyl)benzyl)malonic acid 13

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- phenoxybenzyl)malonic acid15

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- (trifluoromethoxy)benzyl)malonic acid 16

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- (trifluoromethyl)benzyl)malonic acid 17

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(naphthalen-2- ylmethyl)malonicacid 20

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (trifluoromethyl)benzyl)malonic acid 21

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (methylsulfonyl)benzyl)malonic acid 22

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- (dimethylcarbamoyl)benzyl)malonic acid 23

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(thiophen-3- ylmethyl)malonicacid 25

diethyl 2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- (isobutyryloxy)tetrahydrofuran- 2-yl)methoxy)-2-(4-(trifluoromethoxy)benzyl) malonate 27

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- aminobenzyl)malonic acid 28

2-benzyl-2-(((2R,3R,4S,5R)-5- (6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonicacid 32

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-((6- (trifluoromethyl)pyridin-3-yl)methyl)malonic acid 34

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- cyanobenzyl)malonic acid 35

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- cyanobenzyl)malonic acid 36

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (trifluoromethoxy)benzyl)malonic acid 37

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-3-ethoxy-3-oxo-2-(4-(trifluoromethoxy)benzyl) propanoic acid 38

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-3-ethoxy-3-oxo-2-(4-(trifluoromethoxy)benzyl) propanoic acid 39

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (hydroxymethyl)benzyl)malonic acid 40

2-(((2R,3R,4S,5R)-5-(6-amino- 2-azido-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- cyanobenzyl)malonic acid 41

2-(((2R,3R,4S,5R)-5-(2-azido- 6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)-2-(3-cyanobenzyl)malonic acid 42

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-(3-carboxybenzyl)-malonic acid 43

2-(3-(1H-tetrazol-5-yl)benzyl)- 2-(((2R,3R,4S,5R)-5-(6-amino-2-azido-9H-purin-9-yl)-4- fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)malonic acid 44

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- fluorobenzyl)malonic acid 45

diethyl 2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)-2-(3-fluorobenzyl)malonate 46

diethyl 2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-fluorobenzyl)malonate 47

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- fluorobenzyl)malonic acid 48

diethyl 2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-(trifluoromethoxy)benzyl) malonate 49

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- methoxybenzyl)malonic acid50

2-((1H-tetrazol-5-yl)methyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro- 3-hydroxytetrahydrofuran-2-yl)methoxy)malonic acid 51

2-(((2S,3S,4R,5R)-3-amino-5- (6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2- yl)methoxy)-2-benzylmalonic acid 53

2-(3-(1H-tetrazol-5-yl)benzyl)- 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4- fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)malonic acid 54

2-(4-(1H-tetrazol-5-yl)benzyl)- 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)malonic acid 55

2-(((2R,3S,4R,5R)-4-amino-5- (6-amino-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-benzylmalonic acid 56

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3- hydroxybenzyl)malonic acid57

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-carboxy-2-fluorobenzyl)malonic acid 58

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-(4-carboxy-3-fluorobenzyl)malonic acid 59

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((5-(trifluoromethyl)-furan-2- yl)methyl)malonic acid 60

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-(3- fluoro-4-(trifluoromethyl)benzyl) malonic acid 61

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-((3- phenylisoxazol-5-yl)methyl)malonic acid 62

dimethyl 2-(((2R,3R,4S,5R)-5- (6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-(trifluoromethyl)benzyl)malonate 63

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((1-benzyl-1H-pyrazol-4- yl)methyl)malonic acid 64

2-((1H-pyrazol-4-yl)methyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro- 3-hydroxytetrahydrofuran-2-yl)methoxy)malonic acid 65

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (benzyloxy)benzyl)malonicacid 66

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- hydroxybenzyl)malonic acid67

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((2- carboxythiazol-5-yl)methyl)malonic acid 68

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((2- carboxythiazol-4-yl)methyl)malonic acid 69

2-([1,1′-biphenyl]-4-ylmethyl)- 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-3-ethoxy- 3-oxopropanoic acid 70

diethyl 2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-(2-methoxy-2-oxoethyl)benzyl)malonate 71

diethyl 2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- (isobutyryloxy)tetrahydrofuran- 2-yl)methoxy)-2-((5-(methoxycarbonyl)thiophen-3- yl)methyl)malonate 72

diethyl 2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)-2-((5-(methoxycarbonyl)-1-methyl- 1H-pyrazol-3- yl)methyl)malonate 73

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-((5-carboxy-1-methyl-1H-pyrazol-3- yl)methyl)malonic acid 74

2-benzyl-2-(((2R,3R,4S,5R)-5- (2-chloro-6-hydroxy-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonic acid 75

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-cyano-3- fluorobenzyl)malonicacid 76

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((5-carboxythiophen-3- yl)methyl)malonic acid 77

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((5-carboxythiophen-2- yl)methyl)malonic acid 78

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (carboxymethyl)benzyl)malonic acid 79

2-([1,1′-biphenyl]-4-ylmethyl)- 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)malonic acid 80

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-chloro-2-fluorobenzyl)malonic acid 81

2-([1,1′-biphenyl]-4-ylmethyl)- 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4- fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-3-methoxy-3- oxopropanoic acid 82

2-([1,1′-biphenyl]-4-ylmethyl)- 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4- fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-3-methoxy-3- oxopropanoic acid 83

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-((3- carboxyisoxazol-5-yl)methyl)malonic acid 84

2-([1,1′-biphenyl]-4-ylmethyl)- 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-3-ethoxy- 3-oxopropanoic acid 85

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3-chloro-4-methoxybenzyl)malonic acid 86

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- sulfamoylbenzyl)malonic acid87

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-(4-((2-carboxyethyl)carbamoyl) benzyl)malonic acid 88

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((2-carboxybenzofuran-5- yl)methyl)malonic acid 89

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-(2,2,2-trifluoroethoxy)benzyl) malonic acid 90

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-((E)-2-carboxyyinyl)benzyl)malonic acid 91

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (methoxycarbonyl)benzyl)malonic acid 92

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (carboxymethoxy)benzyl)malonic acid 93

2-benzyl-2-(((2R,3R,4S,5R)-5- (2-chloro-6-oxo-1H-purin-9(6H)-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonic acid94

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4-(5-methyl- 1,3,4-oxadiazol-2-yl)benzyl)malonic acid 95

of 2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)- 4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-((2′-cyano-[1,1′-biphenyl]-4-yl)-methyl)malonic acid 96

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2- yl)methoxy)-2-((5- chlorobenzo[b]thiophen-3-yl)methyl)-malonic acid 97

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(benzo[d]thiazol-2-ylmethyl)malonic acid 98

2-(((2R,3R,4S,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(4- (methylcarbamoyl)benzyl)malonic acid 99

Diethyl 2-(((2R,3S,4R,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran- 2-yl)methoxy)-2-benzyl malonate 100 

2-(((2R,3S,4R,5R)-5-(6-amino- 2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-2-(4- carboxybenzyl)malonic acid101 

S)-2-(((2R,3S,4R,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran- 2-yl)methoxy)-2-(1H-tetrazol-5- yl)aceticacid 102 

(R)-2-(((2R,3S,4R,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran- 2-yl)methoxy)-2-(1H-tetrazol-5- yl)aceticacid 103 

(S)-2-(((2R,3S,4R,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran- 2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoic acid 104 

(R)-2-(((2R,3S,4R,5R)-5-(6- amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran- 2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoic acid 105 

(S)-2-(((2R,3S,4R,5R)-5-(6- amino-2-methoxy-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoic acid 106 

(R)-2-(((2R,3S,4R,5R)-5-(6- amino-2-methoxy-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoic acid 107 

Representative compounds of Formula (I) include those in Table 1B:

TABLE 1B Cpd. # Compound 108

109

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186

mixture of diastereomers 187

mixture of diastereomers 188

mixture of diastereomers 189

mixture of diastereomers 190

mixture of diastereomers 191

192

mixture of diastereomers 193

194

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197

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202

203

204

Other compounds of the invention include:

or a pharmaceutically acceptable salt thereof.

Pharmaceutical Preparations

In certain embodiments, the present invention provides a pharmaceuticalpreparation suitable for use in a human patient, comprising any of thecompounds shown above (e.g., a compound of the invention, such as acompound of formula (I), and one or more pharmaceutically acceptableexcipients. In certain embodiments, the pharmaceutical preparations maybe for use in treating or preventing a condition or disease as describedherein.

Any of the disclosed compounds may be used in the manufacture ofmedicaments for the treatment of any diseases or conditions disclosedherein.

Methods of Use

Provided herein are methods of inhibiting CD73 in a cell, comprisingcontacting the cell with a compound of the invention, such as a compoundof formula (I), or a pharmaceutically acceptable salt thereof. Incertain embodiments, contacting the cell occurs in a subject in needthereof, thereby treating a disease or disorder mediated by adenosine.

Also, disclosed herein are methods of treating a disease or a disordermediated by adenosine comprising administering a compound the invention,such as a compound of of Formula (I), or a pharmaceutically acceptablesalt thereof.

Adenosine acts on a variety of immune cells to induce immunosuppression,and the immunosuppressive effects of ectonucleotidases that enhanceadenosine levels are also associated with enhanced infections ofmammalian cells by parasites, fungi, bacteria, and viruses. Apart fromimmunosuppressive effects, adenosine also has a role in modulating thecardiovascular system (as a vasodilator and cardiac depressor), thecentral nervous system (CNS) (inducing sedative, anxiolytic andantiepileptic effects), the respiratory system (inducingbronchoconstriction), the kidney (having biphasic action; inducingvasoconstriction at low concentrations and vasodilation at high doses),fat cells (inhibiting lipolysis), and platelets (as an anti-aggregant).Furthermore, adenosine also promotes fibrosis (excess matrix production)in a variety of tissues. Therefore, improved treatments targeting CD73would provide therapies for treating a wide range of conditions inaddition to cancer, including cerebral and cardiac ischemic disease,fibrosis, immune and inflammatory disorders (e.g., inflammatory gutmotility disorder), neurological, neurodegenerative and CNS disordersand diseases (e.g., depression, Parkinson's disease), and sleepdisorders.

In some embodiments, the disease or the disorder mediated by adenosineis selected from cerebral ischemic disease, cancer, cardiac ischemicdisease, depression, fibrosis, an immune disorder, an inflammatorydisorder (e.g., inflammatory gut motility disorder), neurologicaldisorder or disease, neurodegenerative disorder or disease (e.g.,Parkinson's disease), CNS disorders and diseases, and sleep disorders.

The methods described herein are useful for the treatment of a widevariety of cancers, including bladder cancer, bone cancer, brain cancer(including glioblastoma), breast cancer, cardiac cancer, cervicalcancer, colon cancer, colorectal cancer, esophageal cancer,fibrosarcoma, gastric cancer, gastrointestinal cancer, head & neckcancer, Kaposi's sarcoma, kidney cancer (including renal celladenocarcinoma), leukemia, liver cancer, lung cancer (includingnon-small cell lung cancer, small cell lung cancer, and mucoepidermoidpulmonary carcinoma), lymphoma, melanoma, myeloma, ovarian cancer(including ovarian adenocarcinoma), pancreatic cancer, penile cancer,prostate cancer, testicular germcell cancer, thymoma and thymiccarcinoma.

In some embodiments, the subject has a cancer selected from breastcancer, brain cancer, colon cancer, fibrosarcoma, kidney cancer, lungcancer, melanoma, ovarian cancer, and prostate cancer. In certainembodiments, the subject has a cancer selected from breast cancer, coloncancer, fibrosarcoma, melanoma, ovarian cancer, and prostate cancer. Inother embodiments, the subject has a cancer selected from brain cancer,breast cancer, kidney cancer, lung cancer, melanoma, and ovarian cancer.In yet other embodiments, the subject has breast cancer. In someembodiments, the breast cancer is breast adenocarcinoma. In certainembodiments, the breast cancer is triple-negative breast cancer.

In certain embodiments, the methods for treating or preventing cancercan be demonstrated by one or more responses such as increasedapoptosis, inhibition of tumor growth, reduction of tumor metastasis,inhibition of tumor metastasis, reduction of microvessel density,decreased neovascularization, inhibition of tumor migration, tumorregression, and increased survival of the subject.

In certain embodiments, the disease or the disorder mediated byadenosine is a disease or disorder mediated by CD73 activity. In someembodiments, the compounds of the invention, such as compounds ofFormula (I), are useful as inhibitors of CD73.

In some embodiments, the methods described herein treat or preventcardiovascular disease using inhibitors of CD73. Mutant genes encodingCD73 lead to extensive calcification of lower-extremity arteries andsmall joint capsules, which is associated with increased risk ofcardiovascular disease (Hilaire et al., N Engl. J. Med., 364(5):432-442, 2011).

In some embodiments, the methods disclosed herein treat or preventcancer using inhibitors of CD73. A CD73 small interfering RNA andanti-CD73 monoclonal antibodies showed a significant effect in treatingor preventing cancer (Antonioli et al., Nat. Rev. Cancer, 13: 842-857,2013). A tight correlation exists between CD73 expression and theability of cancer cells to migrate, invade, and adhere to theextracellular matrix (ECM) (Antonioli 2013; Antonioli et al., TrendsCancer, 2(2): 95-109, 2016).

In some embodiments, the treatment or prevention of cancer by inhibitorsof CD73 can be demonstrated by one or more responses selected fromactivation, clonal expansion, and homing of tumor-specific T cells(Antonioli 2016). In other embodiments, the methods disclosed hereinincrease the number of effector T lymphocytes (e.g., cytolytic effectorT lymphocytes).

Combination Treatments

In some embodiments, the method of treating or preventing cancer maycomprise administering a CD39 inhibitor conjointly with one or moreother chemotherapeutic agent(s). In one embodiment, the CD73 inhibitoris a compound of the invention, such as a compound of Formula (I). Otherchemotherapeutic agents can include CD73-specific monoclonal antibodieswhich enhance the effects of other antibodies and therapies because ofincreased overall immune system activity (lower T-regulatory functionand higher T-effector function, etc.) (Antonioli 2016).

In certain embodiments, the method of treating or preventing cancer maycomprise administering a compound of the invention conjointly with oneor more other chemotherapeutic agent(s).

Chemotherapeutic agents that may be conjointly administered withcompounds of the invention include:1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate(acid blue 25),1-amino-444-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-441-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine,anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guérinvaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP(AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin,capecitabine, carboplatin, carfilzomib, carmustine, ceritinib,chlorambucil, chloroquine, cisplatin, cladribine, clodronate,cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone,cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin,dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol,docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, filgrastim,fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide,gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea,idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone,lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine,lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan,mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin,mitotane, mitoxantrone, MK-2206, mutamycin,N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide,nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate,pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin,pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed,ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin,rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate,sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen,temozolomide, temsirolimus, teniposide, testosterone, thalidomide,thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan,trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine,vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments,chemotherapeutic agents that may be conjointly administered withcompounds of the invention include: ABT-263, dexamethasone,5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In otherembodiments, chemotherapeutic agents that may be conjointly administeredwith compounds of the invention include:1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate(acid blue 25),1-amino-4-14-hydroxyphenyl-amino1-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-14-aminophenylamino1-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-11-naphthylamino1-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-fluoro-2-carboxyphenylamino1-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine,fludarabine, doxorubicin, gemcitabine,N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS,quercetin, reactive blue 2, rolofylline sodium2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.

Many combination therapies have been developed for the treatment ofcancer. In certain embodiments, compounds of the invention (e.g.,compounds of Formula (I)) may be conjointly administered with acombination therapy. Examples of combination therapies with whichcompounds of the invention may be conjointly administered are includedin Table 1.

TABLE 1 Exemplary combinatorial therapies for the treatment of cancerName Therapeutic agents ABV Doxorubicin, Bleomycin, Vinblastine ABVDDoxorubicin, Bleomycin, Vinblastine, Dacarbazine AC (Breast)Doxorubicin, Cyclophosphamide AC (Sarcoma) Doxorubicin, Cisplatin AC(Neuroblastoma) Cyclophosphamide, Doxorubicin ACE Cyclophosphamide,Doxorubicin, Etoposide ACe Cyclophosphamide, Doxorubicin AD Doxorubicin,Dacarbazine AP Doxorubicin, Cisplatin ARAC-DNR Cytarabine, DaunorubicinB-CAVe Bleomycin, Lomustine, Doxorubicin, Vinblastine BCVPP Carmustine,Cyclophosphamide, Vinblastine, Procarbazine, Prednisone BEACOPPBleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine,Procarbazine, Prednisone, Filgrastim BEP Bleomycin, Etoposide, CisplatinBIP Bleomycin, Cisplatin, Ifosfamide, Mesna BOMP Bleomycin, Vincristine,Cisplatin, Mitomycin CA Cytarabine, Asparaginase CABO Cisplatin,Methotrexate, Bleomycin, Vincristine CAF Cyclophosphamide, Doxorubicin,Fluorouracil CAL-G Cyclophosphamide, Daunorubicin, Vincristine,Prednisone, Asparaginase CAMP Cyclophosphamide, Doxorubicin,Methotrexate, Procarbazine CAP Cyclophosphamide, Doxorubicin, CisplatinCAV Cyclophosphamide, Doxorubicin, Vincristine CAVE ADD CAV andEtoposide CA-VP16 Cyclophosphamide, Doxorubicin, Etoposide CCCyclophosphamide, Carboplatin CDDP/VP-16 Cisplatin, Etoposide CEFCyclophosphamide, Epirubicin, Fluorouracil CEPP(B) Cyclophosphamide,Etoposide, Prednisone, with or without/Bleomycin CEV Cyclophosphamide,Etoposide, Vincristine CF Cisplatin, Fluorouracil or CarboplatinFluorouracil CHAP Cyclophosphamide or Cyclophosphamide, Altretamine,Doxorubicin, Cisplatin ChlVPP Chlorambucil, Vinblastine, Procarbazine,Prednisone CHOP Cyclophosphamide, Doxorubicin, Vincristine, PrednisoneCHOP-BLEO Add Bleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin,Cisplatin CLD-BOMP Bleomycin, Cisplatin, Vincristine, Mitomycin CMFMethotrexate, Fluorouracil, Cyclophosphamide CMFP Cyclophosphamide,Methotrexate, Fluorouracil, Prednisone CMFVP Cyclophosphamide,Methotrexate, Fluorouracil, Vincristine, Prednisone CMV Cisplatin,Methotrexate, Vinblastine CNF Cyclophosphamide, Mitoxantrone,Fluorouracil CNOP Cyclophosphamide, Mitoxantrone, Vincristine,Prednisone COB Cisplatin, Vincristine, Bleomycin CODE Cisplatin,Vincristine, Doxorubicin, Etoposide COMLA Cyclophosphamide, Vincristine,Methotrexate, Leucovorin, Cytarabine COMP Cyclophosphamide, Vincristine,Methotrexate, Prednisone Cooper Regimen Cyclophosphamide, Methotrexate,Fluorouracil, Vincristine, Prednisone COP Cyclophosphamide, Vincristine,Prednisone COPE Cyclophosphamide, Vincristine, Cisplatin, Etoposide COPPCyclophosphamide, Vincristine, Procarbazine, Prednisone CP(ChronicChlorambucil, Prednisone lymphocytic leukemia) CP (OvarianCyclophosphamide, Cisplatin Cancer) CVD Cisplatin, Vinblastine,Dacarbazine CVI Carboplatin, Etoposide, Ifosfamide, Mesna CVPCyclophosphamide, Vincristine, Prednisome CVPP Lomustine, Procarbazine,Prednisone CYVADIC Cyclophosphamide, Vincristine, Doxorubicin,Dacarbazine DA Daunorubicin, Cytarabine DAT Daunorubicin, Cytarabine,Thioguanine DAV Daunorubicin, Cytarabine, Etoposide DCT Daunorubicin,Cytarabine, Thioguanine DHAP Cisplatin, Cytarabine, Dexamethasone DIDoxorubicin, Ifosfamide DTIC/Tamoxifen Dacarbazine, Tamoxifen DVPDaunorubicin, Vincristine, Prednisone EAP Etoposide, Doxorubicin,Cisplatin EC Etoposide, Carboplatin EFP Etoposie, Fluorouracil,Cisplatin ELF Etoposide, Leucovorin, Fluorouracil EMA 86 Mitoxantrone,Etoposide, Cytarabine EP Etoposide, Cisplatin EVA Etoposide, VinblastineFAC Fluorouracil, Doxorubicin, Cyclophosphamide FAM Fluorouracil,Doxorubicin, Mitomycin FAMTX Methotrexate, Leucovorin, Doxorubicin FAPFluorouracil, Doxorubicin, Cisplatin F-CL Fluorouracil, Leucovorin FECFluorouracil, Cyclophosphamide, Epirubicin FED Fluorouracil, Etoposide,Cisplatin FL Flutamide, Leuprolide FZ Flutamide, Goserelin acetateimplant HDMTX Methotrexate, Leucovorin Hexa-CAF Altretamine,Cyclophosphamide, Methotrexate, Fluorouracil IDMTX/6-MP Methotrexate,Mercaptopurine, Leucovorin IE Ifosfamide, Etoposie, Mesna IfoVPIfosfamide, Etoposide, Mesna IPA Ifosfamide, Cisplatin, Doxorubicin M-2Vincristine, Carmustine, Cyclophosphamide, Prednisone, Melphalan MAC-IIIMethotrexate, Leucovorin, Dactinomycin, Cyclophosphamide MACCMethotrexate, Doxorubicin, Cyclophosphamide, Lomustine MACOP-BMethotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine,Bleomycin, Prednisone MAID Mesna, Doxorubicin, Ifosfamide, Dacarbazinem-BACOD Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine,Dexamethasone, Methotrexate, Leucovorin MBC Methotrexate, Bleomycin,Cisplatin MC Mitoxantrone, Cytarabine MF Methotrexate, Fluorouracil,Leucovorin MICE Ifosfamide, Carboplatin, Etoposide, Mesna MINE Mesna,Ifosfamide, Mitoxantrone, Etoposide mini-BEAM Carmustine, Etoposide,Cytarabine, Melphalan MOBP Bleomycin, Vincristine, Cisplatin, MitomycinMOP Mechlorethamine, Vincristine, Procarbazine MOPP Mechlorethamine,Vincristine, Procarbazine, Prednisone MOPP/ABV Mechlorethamine,Vincristine, Procarbazine, Prednisone, Doxorubicin, Bleomycin,Vinblastine MP (multiple Melphalan, Prednisone myeloma) MP (prostateMitoxantrone, Prednisone cancer) MTX/6-MO Methotrexate, MercaptopurineMTX/6-MP/VP Methotrexate, Mercaptopurine, Vincristine, PrednisoneMTX-CDDPAdr Methotrexate, Leucovorin, Cisplatin, Doxorubicin MV (breastMitomycin, Vinblastine cancer) MV (acute Mitoxantrone, Etoposidemyelocytic leukemia) M-VAC Vinblastine, Doxorubicin, CisplatinMethotrexate MVP Mitomycin Vinblastine, Cisplatin MVPP Mechlorethamine,Vinblastine, Procarbazine, Prednisone NFL Mitoxantrone, Fluorouracil,Leucovorin NOVP Mitoxantrone, Vinblastine, Vincristine OPA Vincristine,Prednisone, Doxorubicin OPPA Add Procarbazine to OPA. PAC Cisplatin,Doxorubicin PAC-I Cisplatin, Doxorubicin, Cyclophosphamide PA-CICisplatin, Doxorubicin PCV Lomustine, Procarbazine, Vincristine PFLCisplatin, Fluorouracil, Leucovorin POC Prednisone, Vincristine,Lomustine ProMACE Prednisone, Methotrexate, Leucovorin, Doxorubicin,Cyclophosphamide, Etoposide ProMACE/ Prednisone, Doxorubicin,Cyclophosphamide, cytaBOM Etoposide, Cytarabine, Bleomycin, Vincristine,Methotrexate, Leucovorin, Cotrimoxazole PRoMACE/MOPP Prednisone,Doxorubicin, Cyclophosphamide, Etoposide, Mechlorethamine, Vincristine,Procarbazine, Methotrexate, Leucovorin Pt/VM Cisplatin, Teniposide PVAPrednisone, Vincristine, Asparaginase PVB Cisplatin, Vinblastine,Bleomycin PVDA Prednisone, Vincristine, Daunorubicin, Asparaginase SMFStreptozocin, Mitomycin, Fluorouracil TAD Mechlorethamine, Doxorubicin,Vinblastine, Vincristine, Bleomycin, Etoposide, Prednisone TTTMethotrexate, Cytarabine, Hydrocortisone Topo/CTX Cyclophosphamide,Topotecan, Mesna VAB-6 Cyclophosphamide, Dactinomycin, Vinblastine,Cisplatin, Bleomycin VAC Vincristine, Dactinomycin, CyclophosphamideVACAdr Vincristine, Cyclophosphamide, Doxorubicin, Dactinomycin,Vincristine VAD Vincristine, Doxorubicin, Dexamethasone VATHVinblastine, Doxorubicin, Thiotepa, Flouxymesterone VBAP Vincristine,Carmustine, Doxorubicin, Prednisone VBCMP Vincristine, Carmustine,Melphalan, Cyclophosphamide, Prednisone VC Vinorelbine, Cisplatin VCAPVincristine, Cyclophosphamide, Doxorubicin, Prednisone VD Vinorelbine,Doxorubicin VelP Vinblastine, Cisplatin, Ifosfamide, Mesna VIPEtoposide, Cisplatin, Ifosfamide, Mesna VM Mitomycin, Vinblastine VMCPVincristine, Melphalan, Cyclophosphamide, Prednisone VP Etoposide,Cisplatin V-TAD Etoposide, Thioguanine, Daunorubicin, Cytarabine 5 + 2Cytarabine, Daunorubicin, Mitoxantrone 7 + 3 Cytarabine with/,Daunorubicin or Idarubicin or Mitoxantrone “8 in 1” Methylprednisolone,Vincristine, Lomustine, Procarbazine, Hydroxyurea, Cisplatin,Cytarabine, Dacarbazine

In some embodiments, the chemotherapeutic agents that may be conjointlyadministered with compounds of the invention, such as a compound ofFormula (I), include a CD39 inhibitor. CD39 or ecto-nucleosidetriphosphate diphosphohydrolase 1 (E-NTPDase1 or ENTPD 1) is amembrane-bound enzyme that catalyzes the conversion of extracellularadenosine triphosphate (ATP) and/or ADP (adenosine diphosphate) toadenosine monophosphate (AMP). In one embodiment, the CD39 inhibitor ispolyoxometalate-1 (POM-1).

In other embodiments, the chemotherapeutic agents that may be conjointlyadministered with compounds of the invention, such as a compound ofFormula (I), include known CD73 inhibitors. In some embodiments, theCD73 inhibitor is an anthraquinone derivative (Baqi et al., J. Med.Chem., 53(5): 2076-2086, 2010, herein incorporated by reference). Inother embodiments, the CD73 inhibitor is an sulfonic acid derivative(Raza et al., Med. Chem., 8: 1133-1139, 2012, herein incorporated byreference). In yet other embodiments, the CD73 inhibitor is selectedfrom 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate(acid blue 25),1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-aminophenylamino1-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-442-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,sodium 2,4-dinitrobenzenesulfonate, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, APCP, O-methylene-ADP (AOPCP), PPADS, NF279, NF449,quercetin, reactive blue 2, and sumarin (Baqi 2010; Raza 2012).

In certain embodiments, the combination of a compound of the invention,such as a compound of Formula (I), with a second CD73 inhibitor or aCD39 inhibitor may have a synergistic effect in the treatment of cancerand other diseases or disorders mediated by adenosine. Without wishingto be bound by any theory, this synergy may be observed because CD39 andCD73 are often on different cell types. The hypoxic tumormicroenvironment also induces greater levels of CD39 and CD73.

In some embodiments, the chemotherapeutic agents that may be conjointlyadministered with compounds of the invention, such as a compound ofFormula (I), include an adenosine receptor inhibitor. In otherembodiments, the adenosine receptor inhibitor is selected fromrolofylline, tonapofylline, ATL-444, istradefylline, MSX-3, preladenant,SCH-58,261, SCH-412,348, SCH-442,416, ST-1535, VER-6623, VER-6947,VER-7835, vipadenant, and ZM-241,385. In some embodiments, the adenosinereceptor inhibitor targets the A2A receptor as this subtype ispredominantly expressed in most immune cells.

In other embodiments, the chemotherapeutic agents that may be conjointlyadministered with compounds of the invention, such as a compound ofFormula (I), include a nucleoside-based drug. In certain embodiments,the nucleoside-based drug is selected from gemcitabine, capecitabine,cytarabine, fludarabine and ciadribine.

In further embodiments, the combination therapy comprises a compound ofthe invention, such as a compound of Formula (I), conjointlyadministered with an anthracycline. In other embodiments, thecombination therapy comprises a compound of the invention, such as acompound of Formula (I), conjointly administered with doxorubicin.Combination treatment with an anti-CD73 antibody and doxorubicin hasdemonstrated a significant chemotherapeutic effect (Young et al., CancerDiscov., 4(8): 1-10, 2014, herein incorporated by reference).

In certain embodiments, the combination therapy comprises a compound ofthe invention, such as a compound of Formula (I), conjointlyadministered with an A2A receptor inhibitor and an anthracycline. Insome embodiments, the anthracycline is doxorubicin. Combinationtreatment with an anti-CD73 antibody, an A_(2A) receptor inhibitor, anddoxorubicin has demonstrated an increased chemotherapeutic effect(Antonioli 2013).

In certain embodiments, the conjoint therapies of the invention compriseconjoint administration with other types of chemotherapeutic agents,such as immuno-oncology agents. Cancer cells often have specific cellsurface antigens that can be recognized by the immune system. Thus,immuno-oncology agents, such as monoclonal antibodies, can selectivelybind to cancer cell antigens and effect cell death. Otherimmuno-oncology agents can suppress tumor-mediated inhibition of thenative immune response or otherwise activate the immune response andthus facilitate recognition of the tumor by the immune system. Exemplaryantibody immuno-oncology agents, include, but are not limited to,abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox,apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. Insome embodiments, the antibody immune-oncology agents are selected fromanti-CD73 monoclonal antibody (mAb), anti-CD39 mAb, anti-PD-1 mAb, andanti-CTLA4 mAb. Thus, in some embodiments, the methods of the inventioncomprise conjoint administration of one or more immuno-oncology agents,such as the agents mentioned above.

In some embodiments, the combination therapy comprises a compound of theinvention, such as a compound of Formula (I), conjointly administeredwith anti-PD-1 therapy and anti-CTLA4 therapy. Combination treatmentwith an anti-CD73 monoclonal antibody (mAb), anti-PD-1 mAb, andanti-CTLA4 mAb showed a significant chemotherapeutic effect (Young 2014;Antonioli 2013).

In certain embodiments, a compound of the invention may be conjointlyadministered with non-chemical methods of cancer treatment. In certainembodiments, a compound of the invention may be conjointly administeredwith radiation therapy. In certain embodiments, a compound of theinvention may be conjointly administered with surgery, withthermoablation, with focused ultrasound therapy, with cryotherapy, orwith any combination of these.

In certain embodiments, compounds of the invention may be conjointlyadministered with one or more other compounds of the invention.Moreover, such combinations may be conjointly administered with othertherapeutic agents, such as other agents suitable for the treatment ofcancer, immunological or neurological diseases, such as the agentsidentified above. In certain embodiments, conjointly administering oneor more additional chemotherapeutic agents with a compound of theinvention provides a synergistic effect. In certain embodiments,conjointly administering one or more additional chemotherapeutic agentsprovides an additive effect.

Pharmaceutical Compositions

The compositions and methods of the present invention may be utilized totreat a subject in need thereof. In certain embodiments, the subject isa mammal such as a human, or a non-human mammal. When administered tosubject, such as a human, the composition or the compound is preferablyadministered as a pharmaceutical composition comprising, for example, acompound of the invention and a pharmaceutically acceptable carrier.Pharmaceutically acceptable carriers are well known in the art andinclude, for example, aqueous solutions such as water or physiologicallybuffered saline or other solvents or vehicles such as glycols, glycerol,oils such as olive oil, or injectable organic esters. In a preferredembodiment, when such pharmaceutical compositions are for humanadministration, particularly for invasive routes of administration(i.e., routes, such as injection or implantation, that circumventtransport or diffusion through an epithelial barrier), the aqueoussolution is pyrogen-free, or substantially pyrogen-free. The excipientscan be chosen, for example, to effect delayed release of an agent or toselectively target one or more cells, tissues or organs. Thepharmaceutical composition can be in dosage unit form such as tablet,capsule (including sprinkle capsule and gelatin capsule), granule,lyophile for reconstitution, powder, solution, syrup, suppository,injection or the like. The composition can also be present in atransdermal delivery system, e.g., a skin patch. The composition canalso be present in a solution suitable for topical administration, suchas an eye drop.

A pharmaceutically acceptable carrier can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as acompound of the invention. Such physiologically acceptable agentsinclude, for example, carbohydrates, such as glucose, sucrose ordextrans, antioxidants, such as ascorbic acid or glutathione, chelatingagents, low molecular weight proteins or other stabilizers orexcipients. The choice of a pharmaceutically acceptable carrier,including a physiologically acceptable agent, depends, for example, onthe route of administration of the composition. The preparation orpharmaceutical composition can be a self-emulsifying drug deliverysystem or a self-microemulsifying drug delivery system. Thepharmaceutical composition (preparation) also can be a liposome or otherpolymer matrix, which can have incorporated therein, for example, acompound of the invention. Liposomes, for example, which comprisephospholipids or other lipids, are nontoxic, physiologically acceptableand metabolizable carriers that are relatively simple to make andadminister.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the subject. Some examples of materials which can serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally (for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules (including sprinkle capsulesand gelatin capsules), boluses, powders, granules, pastes forapplication to the tongue); absorption through the oral mucosa (e.g.,sublingually); anally, rectally or vaginally (for example, as a pessary,cream or foam); parenterally (including intramuscularly, intravenously,subcutaneously or intrathecally as, for example, a sterile solution orsuspension); nasally; intraperitoneally; subcutaneously; transdermally(for example as a patch applied to the skin); and topically (forexample, as a cream, ointment or spray applied to the skin, or as an eyedrop). The compound may also be formulated for inhalation. In certainembodiments, a compound may be simply dissolved or suspended in sterilewater. Details of appropriate routes of administration and compositionssuitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thesubject being treated, the particular mode of administration. The amountof active ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of onehundred percent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association an active compound, such as a compound ofthe invention, with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the present inventionwith liquid carriers, or finely divided solid carriers, or both, andthen, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules (including sprinkle capsules and gelatin capsules),cachets, pills, tablets, lozenges (using a flavored basis, usuallysucrose and acacia or tragacanth), lyophile, powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a compound of the present invention as anactive ingredient. Compositions or compounds may also be administered asa bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules(including sprinkle capsules and gelatin capsules), tablets, pills,dragees, powders, granules and the like), the active ingredient is mixedwith one or more pharmaceutically acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; (10) complexing agents,such as, modified and unmodified cyclodextrins; and (11) coloringagents. In the case of capsules (including sprinkle capsules and gelatincapsules), tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions, such as dragees, capsules (including sprinkle capsules andgelatin capsules), pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions that can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, cyclodextrins and derivatives thereof, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions for rectal, vaginal, orurethral administration may be presented as a suppository, which may beprepared by mixing one or more active compounds with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active compound.

Formulations of the pharmaceutical compositions for administration tothe mouth may be presented as a mouthwash, or an oral spray, or an oralointment.

Alternatively or additionally, compositions can be formulated fordelivery via a catheter, stent, wire, or other intraluminal device.Delivery via such devices may be especially useful for delivery to thebladder, urethra, ureter, rectum, or intestine.

Formulations which are suitable for vaginal administration also includepessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. The active compound may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the active compound in theproper medium. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat.No. 6,583,124, the contents of which are incorporated herein byreference. If desired, liquid ophthalmic formulations have propertiessimilar to that of lacrimal fluids, aqueous humor or vitreous humor orare compatible with such fluids. A preferred route of administration islocal administration (e.g., topical administration, such as eye drops,or administration via an implant).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions suitable for parenteral administrationcomprise one or more active compounds in combination with one or morepharmaceutically acceptable sterile isotonic aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

For use in the methods of this invention, active compounds can be givenper se or as a pharmaceutical composition containing, for example, 0.1to 99.5% (more preferably, 0.5 to 90%) of active ingredient incombination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinacious biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired therapeutic responsefor a particular patient, composition, and mode of administration,without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound(s) being employed, the duration of the treatment,other drugs, compounds and/or materials used in combination with theparticular compound(s) employed, the age, sex, weight, condition,general health and prior medical history of the subject being treated,and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the pharmaceutical composition orcompound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved. By “therapeutically effective amount” ismeant the concentration of a compound that is sufficient to elicit thedesired therapeutic effect. It is generally understood that theeffective amount of the compound will vary according to the weight, sex,age, and medical history of the subject. Other factors which influencethe effective amount may include, but are not limited to, the severityof the subject's condition, the disorder being treated, the stability ofthe compound, and, if desired, another type of therapeutic agent beingadministered with the compound of the invention. A larger total dose canbe delivered by multiple administrations of the agent. Methods todetermine efficacy and dosage are known to those skilled in the art(Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in thecompositions and methods of the invention will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments of the presentinvention, the active compound may be administered two or three timesdaily. In preferred embodiments, the active compound will beadministered once daily.

In certain embodiments, the dosing follows a 3+3 design. The traditional3+3 design requires no modeling of the dose—toxicity curve beyond theclassical assumption for cytotoxic drugs that toxicity increases withdose. This rule-based design proceeds with cohorts of three patients;the first cohort is treated at a starting dose that is considered to besafe based on extrapolation from animal toxicological data, and thesubsequent cohorts are treated at increasing dose levels that have beenfixed in advance. In some embodiments, the three doses of a compound offormula (I) range from about 100 mg to about 1000 mg orally, such asabout 200 mg to about 800 mg, such as about 400 mg to about 700 mg, suchas about 100 mg to about 400 mg, such as about 500 mg to about 1000 mg,and further such as about 500 mg to about 600 mg. Dosing can be threetimes a day when taken with without food, or twice a day when taken withfood. In certain embodiments, the three doses of a compound of formula(I) range from about 400 mg to about 800 mg, such as about 400 mg toabout 700 mg, such as about 500 mg to about 800 mg, and further such asabout 500 mg to about 600 mg twice a day. In certain preferredembodiments, a dose of greater than about 600 mg is dosed twice a day.

If none of the three patients in a cohort experiences a dose-limitingtoxicity, another three patients will be treated at the next higher doselevel. However, if one of the first three patients experiences adose-limiting toxicity, three more patients will be treated at the samedose level. The dose escalation continues until at least two patientsamong a cohort of three to six patients experience dose-limitingtoxicities (i.e., >about 33% of patients with a dose-limiting toxicityat that dose level). The recommended dose for phase II trials isconventionally defined as the dose level just below this toxic doselevel.

In certain embodiments, the dosing schedule can be about 40 mg/m² toabout 100 mg/m², such as about 50 mg/m² to about 80 mg/m², and furthersuch as about 70 mg/m² to about 90 mg/m² by IV for 3 weeks of a 4 weekcycle.

In certain embodiments, compounds of the invention may be used alone orconjointly administered with another type of therapeutic agent. As usedherein, the phrase “conjoint administration” refers to any form ofadministration of two or more different therapeutic compounds such thatthe second compound is administered while the previously administeredtherapeutic compound is still effective in the body (e.g., the twocompounds are simultaneously effective in the subject, which may includesynergistic effects of the two compounds). For example, the differenttherapeutic compounds can be administered either in the same formulationor in a separate formulation, either concomitantly or sequentially. Incertain embodiments, the different therapeutic compounds can beadministered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72hours, or a week of one another. Thus, a subject who receives suchtreatment can benefit from a combined effect of different therapeuticcompounds.

In certain embodiments, conjoint administration of compounds of theinvention with one or more additional therapeutic agent(s) (e.g., one ormore additional chemotherapeutic agent(s)) provides improved efficacyrelative to each individual administration of the compound of theinvention (e.g., compound of formula I or Ia) or the one or moreadditional therapeutic agent(s). In certain such embodiments, theconjoint administration provides an additive effect, wherein an additiveeffect refers to the sum of each of the effects of individualadministration of the compound of the invention and the one or moreadditional therapeutic agent(s).

This invention includes the use of pharmaceutically acceptable salts ofcompounds of the invention in the compositions and methods of thepresent invention. In certain embodiments, contemplated salts of theinvention include, but are not limited to, alkyl, dialkyl, trialkyl ortetra-alkyl ammonium salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, L-arginine,benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol,diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine,ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium,L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine,potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine,tromethamine, and zinc salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, Na, Ca, K, Mg, Zn orother metal salts.

The pharmaceutically acceptable acid addition salts can also exist asvarious solvates, such as with water, methanol, ethanol,dimethylformamide, and the like. Mixtures of such solvates can also beprepared. The source of such solvate can be from the solvent ofcrystallization, inherent in the solvent of preparation orcrystallization, or adventitious to such solvent.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

General Synthesis

Compound numbers 1-45 as used in the general synthesis section belowrefer only to genus structures in this section and do not apply tocompounds disclosed elsewhere in this application. Compounds disclosedherein can be made by methods depicted in the reaction schemes below.

The starting materials and reagents used in preparing these compoundsare either available from commercial supplier such as Aldrich ChemicalCo., Bachem, etc., or can be made by methods well known in the art. Theschemes are merely illustrative of some methods by which the compoundsdisclosed herein can be synthesized and various modifications to theseschemes can be made and will be suggested to POSITA having referred tothis disclosure. The starting materials and the intermediates and thefinal products of the reacton may be isolated and purified if desiredusing convential techniques, including but not limited to filtration,distillation, crystallization, chromatography, and the like and may becharacterized using conventional means, including physical constants andspectral data.

Unless specified otherwise, the reactions described herein take place atatmospheric pressure over a temperature range from about −78° C. toabout 150° C.

Compounds of Formula (I) having the structure:

where R^(u), R^(v), R⁵, and R⁹ are as defined in the Summary can besynthesized as illustrated and described in Scheme 1 below.

Removal of the benzoyl groups in a compound of formula 1 with a suitablebase such as NH₃ in an organic alcohol solvent such as MeOH, or aq. LiOHor aq. NaOH, followed by selectively protecting the 5′-OH group withtert-butyldiphenylsilyl group provides a compound of formula 2.

Compounds of formula 1 are either commercially available or they can beprepared by methods well known in the art. For example,((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methylbenzoate and((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2-amino-6-chloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methylbenzoate are commercially available. Compounds of formula 1 where R^(u)is other than chloro or amino and R^(v) is other than chloro can beprepared from((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methylbenzoate as described in PCT application publication nos. WO 2015/164573and WO 2017/120508.

Protection of the 3′-hydroxy group in compound 2 with a suitable hydroxyprotecting group such as Boc, followed by removal of the silyl groupunder conditions well known in the art such as TBAF in THF provides acompound of formula 4. Reaction of compound 4 with a diazo reagent offormula 5 where R⁹ is unsubstituted alkyl or benzyl in the presence ofcatalyst, such as Rh₂(OAc)₄ or CuOAc₂ in a suitable organic solvent suchas toluene, benzene, dichloromethane, dichloroethane, and THF, providesa compound of Formula 6 where R⁵ is hydrogen. Compound 6 can then beconverted to a compound of Formula (I) by removal of the Boc group underacidic hydrolysis conditions, followed by removal of the R⁹ group underbasic hydrolysis reaction condition e.g, aq. LiOH or NaOH (when R⁹ isalkyl) or by hydrogenolysis with Pd/C or Pd(OH)₂/C (when R⁹ is benzyl).

Alternatively, compound 6 can be reacted with a halide of formula R⁵Xwhere X is halo (preferably chloro, bromo, iodo, tosylate, mesylate ortriflate) and R⁵ is as defined in the Summary except hydrogen underalkylating reaction conditions to provide a corresponding compound ofFormula (I) where R⁵ and R⁹ are other than hydrogen which can then beconverted to corresponding compound of Formula (I) where R⁹ are hydrogenas described above.

Compounds of Formula (I) where Het is other than purine can be preparedby methods well known in the art. For example, compounds of Formula (I)where is a group of formula (i), (ii), or (vii) can be prepared from2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine,4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine and4,6-dichloro-1H-imidazo[4,5-c]pyridine respectively, by syntheticprocedures disclosed in PCT application publication no. WO 2017/120508and Scheme 1 above.

Proceeding as described above but substituting compound of formula 1,with(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-chloro-2-(hydroxymethyl)-tetrahydrofuran-3-ol(prepared according to the procedures reported by Secrist, John A., IIIet al, Journal of Medicinal Chemistry, 31(2), 405-10; 1988 and byAnderson, Bruce G. et al.,Organic Process Research & Development, 12(6),1229-1237; 2008), compounds of Formula (I) where R^(1a) is chloro,R^(1b) and R^(2b) are hydrogen, and R^(2a) is hydroxy and Het is2-chloro-9H-purin-6-amine can be prepared. It will be apparent to aperson skilled that analogs of such compounds i.e, Het is other than2-chloro-9H-purin-6-amine can also be prepared based on the disclosureof this Application and methods known in the art.

Proceeding as described above but substituting compound of formula 1,with(2R,3S,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-5-(hydroxymethyl)-tetrahydrofuran-3-ol(prepared according to procedures reported by Ren, Hang et al BeilsteinJournal of Organic Chemistry, 11, 2509-2520; 2015, and by Schinazi,Raymond F. et al., Heterocyclic Communications, 21(5), 315-327; 2015)compounds of Formula (I) where R^(1a) is hydroxy, R^(1b) and R^(2b) arehydrogen, and R^(2a) is fluoro and Het is 2-chloro-9H-purin-6-amine canbe prepared. It will be apparent to a person skilled that analogs ofsuch compounds i.e, Het is other than 2-chloro-9H-purin-6-amine can alsobe prepared based on the disclosure of this Application and methodsknown in the art.

Proceeding as described above but substituting compound of formula 1,with((2R,3R,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-difluorotetrahydrofuran-2-yl)methanol(prepared according to procedures reported by Schinazi, Raymond F. etal., Heterocyclic Communications, 21(5), 315-327; 2015 and by Sivets,Grigorii G. et al., Nucleosides, Nucleotides & Nucleic Acids, 28(5-7),519-536; 2009) compounds of Formula (I) where R^(1b) is fluoro, R^(1a)and R^(2a) are hydrogen, and R^(2b) is fluoro and Het is2-chloro-9H-purin-6-amine can be prepared. It will be apparent to aperson skilled that analogs of such compounds i.e, Het is other than2-chloro-9H-purin-6-amine can also be prepared based on the disclosureof this Application and methods known in the art.

Proceeding as described above but substituting compound of formula 1,with(2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol(prepared according to the procedures reported by Franchetti, Palmarisa,et al., J. Med. Chem., 48(15), 4983-4989, 2005), or(2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3,4-diol(prepared according to the procedures reported by Hulpia, Fabian et al.,Bioorganic & Medicinal Chemistry Letters, 26(8), 1970-1972; 2016)compounds of Formula (I) where R^(1a) and R^(2a) are hydroxy, R^(1b) ishydrogen, and R^(2b) is methyl or ethynyl respectively, and Het is2-chloro-9H-purin-6-amine can be prepared. It will be apparent to aperson skilled that analogs of such compounds i.e, Het is other than2-chloro-9H-purin-6-amine can also be prepared based on the disclosureof this Application and methods known in the art.

Compounds of Formula (I) having the structure:

where R^(1a) is halo, alkyl, alkynyl, alkenyl, or cyano, R^(1b) is haloor hydroxy, or R^(1a) and R^(1b) are fluoro, Het is a ring of formula(iii) where R^(s) is hydrogen, and R^(u) and R^(v) are as defined in theSummary and R⁵ and R⁹ are as defined in the Summary can be synthesizedby proceeding as described in Scheme 2 below.

Compounds of Formula (I) where R^(1a) is halo, alkyl, alkynyl, alkenyl,or cyano, R^(1b) is halo or hydroxy, or R^(1a) and R^(1b) are fluoro,Het is a ring of formula (iii) where R^(s) is hydrogen, and R^(u) andR^(v) are as defined in the Summary and R⁵ and R⁹ are as defined in theSummary can prepared from compounds of formula 7 as illustrated inScheme 2 above by proceeding under the reaction conditions described inScheme 1 above.

Compounds of formula 1 are either commercially available or they can beprepared by methods known in the art. For example, compound of formula 7(2R,3R,4R,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diolis commercially available or can be prepared according to procedurereported by Caballero, Gerado et al., Helvetica Chimica Acta, 85(5),1284-1294; 2002 and by Li, Nan-Sheng et al., J. Org. Chem., 74(5),2227-2230, 2009).(2R,3R,4R,5R)-2-(6-Amino-2-chloro-9H-purin-9-yl)-3-ethynyl-5-(hydroxymethyl)tetrahydrofuran-3,4-diolcan be prepared according to procedures reported by Nadler, Andre andDiedrerichsen, Ulf., European Journal of Organic Chemistry, 9,1544-1549; 2008.(2R,3R,4R,5R)-2-(6-Amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)-3-vinyltetrahydrofuran-3,4-diolcan be prepared according to procedures reported by Blatt, Lawrence M.et al., U.S. Pat. Appl. Publ. No. 20150366888, and by Carroll, Steven S.et al., PCT Int. Appl., publication no. WO 2004000858.(2R,3R,4R,5R)-2-(6-Amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-3-carbonitrilecan be prepared according to procedures reported by Ohtawa, Masaki etal., J. Med. Chem, 50(9), 2007-2009; 2007.

(2R,3R,4R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-olis commercially available.(2R,3R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-ylbenzoate can be prepared by reacting((2R,3R)-3-(benzoyloxy)-4,4-difluoro-5-iodotetrahydrofuran-2-yl)methylbenzoate and 2-chloroadenine under the Vorbrueggen conditions [(i)(CH₃Si)₂NH, (NH₄)₂SO₄ or Me3SiN═CMeOSiMe₃, (ii) TMSOTf, refluxing]according to the procedure reported by Vorbrueggen, Helmut & Ruh-Polenz,Carmen, Organic Reactions, 55, 2000 and by Beigelman, Leonid, et al., USpatent application, publication No. US 2013/0165400, followed by removalof the benzoyl groups in the resulting compound(2R,3R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-ylbenzoate as described below.

Compounds of Formula (I) where Het is other than purine can be preparedfrom commercially available starting materials as described in Scheme 1above.

Compounds of Formula (I) having the structure:

where R^(1a) is alkyl, alkynyl, vinyl, or cyano, Het is a ring offormula (iii) where R^(s) is hydrogen, and R^(u) and R^(v) are asdefined in the Summary and R⁵ and R⁹ are as defined in the Summary canbe synthesized by proceeding as illustrated and described in arepresentative example in Scheme 3 below.

Selective protection of the 4′,5′-diol in a compound of formula 12 with1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane, followed by acylation of2′-OH in the resulting compound 13 with a suitable reagent such as1,1′-thiocarbonyldiimidazole, O-phenyl chloro thioformate, or methylchloro oxoacetate provides a compound of formula 14. Compound 14 isconverted to a compound of formula 15 where R^(1b) is hydrogen viadeoxygenation of 2′-OH. The deoxygenation reaction is carried out byheating 14 in the presence of Bu₃SnH and AIBN at high temperature e.g.,in refluxing toluene. Protection of amino group in compound 15, followedby removal of the silyl protecting group provides a compound of formula16 which is then converted into a compound of Formula (I) as describedin Scheme 1 above.

Compound of formula (I) where R^(1a) is ethynyl can be converted to thecorresponding compound of formula (I) where R^(1a) is vinyl viareduction of the ethynyl group with Lindlar catalyst in the presence ofhydrogen.

Compounds of formula 12 such as(2R,3R,4R,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diolis commercially available.(2R,3R,4R,5R)-2-(6-Amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)-3-vinyltetrahydrofuran-3,4-diolcan be prepared according to procedures reported by Blatt, Lawrence M.et al., U.S. Pat. Appl. Publ., No. 20150366888; or by Carroll, Steven S.et al., PCT Int. Appl., publication No. 2004000858; and(2R,3R,4R,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-5-(hydroxyl-methyl)tetrahydro-furan-3-carbonitrilecan be prepared according to procedures reported by Ohtawa, Masaki etal., J. Med. Chem, 50(9), 2007-2009; 2007.

Compounds of Formula (I) having the structure:

where R^(1a) is alkyl, alkynyl, vinyl, or cyano, R^(1b) is hydroxy orhalo; or R^(1a) and R^(1b) are fluoro; Het is a ring of formula (iii)and R^(u), R^(v), R⁵ and R⁹ are as defined in the Summary can besynthesized by proceeding as illustrated and described in arepresentative example in Scheme 4 below.

Selective protection of the primary alcohol in compound 17 with a silylprotecting group such as TBDPSC1, followed by acylation and removal ofthe 3′-OH in resulting compound 18 as described in Scheme 3 aboveprovides a compound of formula 20. Treatment of compound 20 with Boc₂O,followed by removal of the silyl group provides a compound of formula 21which is then converted to a compound of Formula (I) as described inScheme 1 above. Compound of formula (I) where R^(1a) is ethynyl can beconverted to the corresponding compound of formula (I) where R^(1a) isvinyl via reduction of the ethynyl group with Lindlar catalyst in thepresence of hydrogen.

Compounds of formula 17 are either commercially available or they can beprepared by methods known in the art. For example,(2R,3R,4R,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diolis commercially available .(2R,3R,4R,5R)-2-(6-Amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)-3-vinyltetrahydrofuran-3,4-diolcan be prepared according to procedures reported by Blatt, Lawrence M.et. al in U.S. Pat. Appl. Publ. No. 20150366888 or by Carroll, Steven S.et al, in PCT Int. Appl., Publication No., WO2004000858; and(2R,3R,4R,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-3-carbonitrilecan be prepared according to procedures reported by Ohtawa, Masaki etal., J. Med. Chem, 50(9), 2007-2009; 2007.

Compounds of Formula (I) having the structure:

where R^(1a) is hydrogen or alkyl, R^(1b) is hydroxy or halo; R^(2a) isazido or NH₂ and R^(2b) is hydrogen, R³ is hydrogen, Het is a ring offormula (iii), and R^(u), R^(v), R⁵ and R⁹ are as defined in the Summarycan be synthesized by proceeding as illustrated and described in arepresentative example in Scheme 5 below.

Compound 23 is synthesized by first converting the 3′-OH group incompound 22 to a ketone with a suitable oxidizing agent such asDess-Martine periodinane, Swem, Moffet, PDC, or SO₃.pyridine, followedby reduction of the keto group with a suitable reducing agent such assodium borohydride. Compound 22 can be prepared according to theprocedure reported by Koole, L. H. et al., Acta Chemica Scandinavica,43, 665-669, 1989. The 3′-OH group in compound 23 is then converted tothe corresponding azide compound 24 by first converting 3′-OH to asuitable leaving group such as mesylate, tosylate or triflate underreaction conditions well known in the art, followed by displacement ofthe leaving group with sodium azide.

After protecting the 6-amino group in compound 24 with suitableprotecting group such as tert-butoxycarbonyl, the 4-methoxytrityl groupis selectively removed with an acid such as TFA to provide compound 25.Compound 25 is then converted to compound of formula 27 as described inScheme 1 above. Sequential removal of the TBDMS and Boc groups incompound 27 is achieved with treatment with TBAF, followed by treatmentwith TFA to give a compound of Formula (I) where R^(2a) is azido and R⁹is alkyl group which can then be converted to corresponding compounds ofFormula (I) where R⁹ is hydrogen as described in Scheme 1 above.Compounds of Formula (I) where R^(2a) is azido can also be converted tocorresponding compounds of Formula (I) where R^(2a) is amino undersuitable hydrogenation reaction conditions such as H₂, Pd/C, Pd(OH)₂/Cor Lindlar catalyst.

Compounds of Formula (I) having the structure:

where R^(1a) is azido or NH₂; Het is a ring of formula (iii) and R^(u),R^(v), R⁵ and R⁹ are as defined in the Summary can be synthesized byproceeding as illustrated and described in a representative example inScheme 6 below.

Compound 28 is first converted to compound 30 according to the proceduredescribed in Scheme 5 above. Compound 28 can be prepared according tothe procedure reported by Secrist, John A., III et al., Journal ofMedicinal Chemistry, 31(2), 405-10; 1988. Compound 31 is obtained fromcompound 30 via a 4-step process. The bis-silyl protecting group on the3′,5′-diol of compound 30 is first removed by treatment of TBAF and thenthe primary alcohol is protected as a TBDPS ether. Further protection ofthe 3′-OH and 6-NH₂ groups with Boc₂O, followed by removal of the TBDPSether with TBAF affords compound 31. Compound 31 is converted to to acompound of Formula (I) as described in Schemes 1 and 5 above.

Compounds of Formula (I) having the structure:

where R^(1a) is azido or NH₂, Het is a ring of formula (iii) where R^(s)is hydrogen, and R^(u), R^(v), R⁵ and R⁹ are as defined in the Summarycan be synthesized by proceeding as illustrated and described in arepresentative example in Scheme 7 below.

Compounds of Formula (I) as shown above, from compound 32 by firstconverting it into compound 35 as described in Scheme 7. Compound 35 isthen converted to a compound of Formula (I) by following the reactionconditions described in Scheme 1. Compound 32 can be prepared accordingto the procedure reported by Koole, L. H. et al., Acta ChemicaScandinavica, 43, 665-669, 1989.

Proceeding as described in Scheme 7 above, but substituting compound 32with compounds(2R,3R,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)-oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)-tetrahydrofuran-3-ol,

and(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)-tetrahydrofuran-3-ol,

compounds of Formula (I) where

where R⁵ is as defined in the Summary respectively, can be synthesized.

(2R,3R,4R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)-tetrahydrofuran-3-oland(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)-tetrahydrofuran-3-olwhich can be prepared according to reported procedure described inKoole, L. H. et al, Acta Chemica Scandinavica, 43, 665-669, 1989.

Compounds of Formula (I) having the structure:

where R^(1a) and R^(2a), or R^(1a) and R^(2b), or R^(1b) and R^(2b), orR^(1a), R^(2a), R^(1b) and R^(2b) are fluoro, Het is a ring of formula(iii), and R^(u), R^(v), R⁵ and R⁹ are as defined in the Summary can besynthesized by proceeding as illustrated and described in arepresentative example in Scheme 8 below.

Treatment of compound 36 with 2-chloro-6H-purin-6-amine according to theprocedure reported by Sari, Ozkan. et al., Tetrahedron Letters, 58(7),642-644; 2017 provides compound 37. Protection of the amino group withtert-butoxycarbonyl, followed by removal of the benzyl group provideprimary alcohol compound 39 which is converted to a compound of Formula(I) as described in Scheme 1 above.

Compounds of Formula (I) having the structure:

where R^(2a) is alkyl, alkynyl, or cyano, Het is a ring of formula (iii)where R^(s) is hydrogen, and R^(u) and R^(v) and R⁵ is as defined in theSummary can be synthesized by proceeding as illustrated and described ina representative example in Scheme 9 below.

Selective protection of the primary alcohol in a compound of formula 40with a suitable protecting group such tributyl diphenylsilyl, followedby treatment of the resulting silyl compound with Boc₂O under reactionconditions described above provides a compound of formula 41.Deoxygenation of the 3′-hydroxy under conditions described in Scheme 4above provides a compound of formula 42 which is then converted into acompound of Formula (I) as described in Scheme 1 above.

Compound of formula 40 can be prepared by methods well known in the art.(2R,3S,4R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diolcan be prepared according to the procedure reported by Franchetti,Palmarisa, et al., J. Med. Chem., 48(15), 4983-4989, 2005).(2R,3S,4R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-3-ethynyl-2-(hydroxymethyl)-tetrahydrofuran-3,4-diolcan be prepared according to the procedure reported by Hulpia, Fabian etal., Bioorganic & Medicinal Chemistry Letters, 26(8), 1970-1972; 2016.

(2R,3S,4R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-3-carbonitrilecan be prepared from(2R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)-oxy)-2-(((tert-butyldimethylsilyl)oxy)-methyl)dihydrofuran-3(2H)-oneand NaCN according to the similar procedure reported by Camarasa, MariaJose et al., Journal of Medicinal Chemistry, 32(8), 1732-8; 1989 or from2-chloro-2′-arabino-fluoro-2′-deoxyadenosine according to the procedurereported by Ohtawa, Masaki et al., J. Med. Chem., 50(9), 2007-2010,2007.

A compound of Formula (I):

where R^(1a) is hydrogen and R^(1b) is hydroxyl or R^(1a) is fluoro andR^(1b) is hydrogen, R³ is alkyl or aralkyl, Het is a ring of formula(iii) where R^(s) is hydrogen, and R^(u), R^(v), R⁵ and R⁹ are asdefined in the Summary can be synthesized as illustrated and describedin Scheme 10 below.

Conversion of primary alcohol group in a compound of formula 43 with asuitable oxidizing reagent such as Dess-Martin periodinane, Swern,Moffet, or PDC provides an aldehyde compound of formula 44. Compound 44is reacted with a lithium or Grignard reagent of formula R³Li or R³MgXwhere R³ is alkyl or aralkyl and X is halo under conditions well knownin the art to provide a compound of formula 45. Compound 45 is thenconverted to a compound of Formula (I) as described in Scheme 1 above.

The foregoing compound numbers refer soley to the genus structures inthe above general synthesis section and not to the compounds disclosedelsewhere in the application.

SYNTHETIC EXAMPLES Example 1 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Step 1:

To a solution of 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (3.00 g,9.9 mmol) in DMF (10 mL) at 0° C. was added imidazole (1.68 g, 24.7mmol) and followed by TBDPSCl (3.00 mL, 11.7 mmol) dropwise. Thereaction mixture was allowed to warm up to room temperature and stirredfurther for 8 h before it was quenched with H₂O (50 mL) and extractedwith EtOAc (3×50 mL). The combined organic layer was washed further withH₂O (2×100 mL), brine, dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel column chromatography (0-20% EtOAc inhexanes) to provide (2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-fluorotetrahydrofuran-3-ol(4.10 g).

Step 2:

To a solution of (2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-fluorotetrahydrofuran-3-ol(4.10 g, 7.56 mmol) in DMF (10 mL) at room temperature was added Et₃N(3.48 mL, 25.0 mmol), 4-DMAP (150 mg, 1.2 mmol) and Boc₂O (5.20 g, 23.8mmol). The reaction mixture was stirred for 16 h before it was dilutedwith EtOAc (200 mL) and H₂O (100 mL). The organic layer was separated,washed with H₂O (2×100 mL), brine, dried over Na₂SO₄ and concentrated.The residue was purified by silica gel column chromatography (0-20%EtOAc in hexanes) to provideN6,N6-bis-(tert-butoxycarbonyl)-5′-O-(tert-butyldiphenylsilyl)-2′-arabino-fluoro-2′-deoxy-3′-O-(tert-butoxycarbonyl)-2-chloro-adenosine(5.58 g).

Step 3:

N6,N6-Bis-(tert-butoxycarbonyl)-5′-O-(tert-butyldiphenylsilyl)-2′-arabino-fluoro-2′-deoxy-3′-O-(tert-butoxycarbonyl)-2-chloro-adenosine(5.58 g, 6.6 mmol) was dissolved in THF (10 mL) at 0° C. and followed byaddition of a solution of TBAF (10 mL, 10 mmol, 1 M in THF) dropwise.The reaction mixture was stirred from 0° C. to room temperature over 2.5h before it was evaporated to dryness. The residue was purified bysilica gel column chromatography (0-20% EtOAc in hexanes) to provideN6,N6-bis-(tert-butoxycarbonyl)-5′-O-(tert-butyldiphenylsilyl)-2′-arabino-fluoro-2′-deoxy-3′-O-(tert-butoxycarbonyl)-2-chloro-adenosine-fluoro-2′-deoxy-3′-O-(tert-butoxycarbonyl)-2-chloro-adenosine(3.15 g).

Step 4:

To a solution ofN6,N6-bis-(tert-butoxycarbonyl)-2′-fluoro-2′-deoxy-3′-O-(tert-butoxycarbonyl)-2-chloro-adenosine(800 mg, 1.32 mmol) in toluene (2 mL) was added diethyl 2-diazomalonate(321 mg, 1.72 mmol) and Rh₂(OAc)₄ (59 mg, 0.13 mmol) under argonatmosphere. The resulting mixture was stirred at 95° C. for 2 h beforeit was allowed to cool to room temperature. The organic volatile wasremoved under reduced pressure. The resulting crude was purified bysilica gel column chromatography (0-20% EtOAc in hexanes) to providediethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonateas a foam (770 mg).

Step 5:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-malonate(300 mg, 0.394 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added TFA (3 mL). Theresulting mixture was allowed to warm up to room temperature and stirredfor 2 h before it was concentrated under reduced pressure to providecrude diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate.

Step 6:

To a solution of crude diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate(0.394 mmol) in THF (2 mL) and H₂O (2 mL) at room temperature was addedLiOH monohydrate (200 mg). The resulting mixture was stirred overnightbefore it was cooled to 0° C. and acidified to pH ˜6 with 1N HCl (aq)solution and concentrated under reduced pressure. The crude residue waspurified by preparative reversed-phase HPLC to provide 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid as a white solid.

¹H NMR (D₂O, 300 MHz) δ 8.47 (d, J=1.8 Hz, 1H), 6.46 (dd, J=4.4, 13.1Hz, 1H), 5.27 (t, J=8.5 Hz, 1H), 4.60-4.72 (m, 2H), 4.15 (q, J=4.6 Hz,1H), 3.86-4.03 (m, 2H); LC/MS [M+H]=406.

Example 2 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Step 1:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(170 mg, 0.223 mmol) in DMF (2 mL) at 25° C. was added Cs₂CO₃ (145 mg,0.446 mmol). The reaction mixture was stirred for 30 min and followed byaddition of BnBr (53 uL, 0.446 mmol). The reaction mixture was stirredfor 3.5 h before it was diluted with H₂O (20 mL) and extracted withEtOAc (3×30 mL). The combined organic layer was washed further with H₂O(2×40 mL), brine, dried over Na₂SO₄ and concentrated. The resultingcrude was purified by silica gel column chromatography (0-16% EtOAc inhexanes) to provide diethyl 2-4(2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluoro-tetrahydrofuran-2-yl)methoxy)-2-benzylmalonateas a foam.

Step2:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(200 mg, 0.235 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added TFA (2 mL). Theresulting mixture was stirred at room temperature for 2.5 h before itwas concentrated under reduced pressure to provide diethyl diethyl2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonate.

Step3:

To a solution of crude 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonatein THF (2 mL) and H₂O (2 mL) at 0° C. was added LiOH monohydrate (150mg). The resulting mixture was stirred at room temperature overnightbefore it was cooled to 0° C. and acidified to pH ˜6 with 1N HCl (aq)solution and concentrated under reduced pressure. The crude residue waspurified by preparative reversed-phase HPLC to provide 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxy-tetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid as a white solid.

¹H NMR (D₂O, 300 MHz) δ 8.27 (bs, 1H), 8.16 (s, 1H), 7.11 (bs, 5H), 6.35(dd, J=4.3, 13.5 Hz, 1H), 5.17-5.36 (m, 1H), 4.53-4.56 (m, 1H),4.18-4.28 (m, 1H), 3.70-3.85 (m, 2H), 3.24 (s, 2H); LC/MS [M+H]=496.

Example 3 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with methyl 4-(bromomethyl)benzoate provided 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.33 (d, J=2 Hz, 1H), 7.78-7.81 (d, J=8.3 Hz,2H), 7.38-7.41 (d, J=8.3 Hz, 2H), 6.41-6.47 (dd, J=4.5, 13.6 Hz, 1H),5.07-5.28 (dt, J=4.1, 52 Hz, 1H), 4.64-4.73 (dt, J=4.2, 18.0 Hz, 1H),4.15-4.19 (q, J=4.6 Hz, 1H), 3.93-4.10 (m, 2H), 3.42-3.55 (m, 2H); LC/MS[M−H]=538.

Example 4 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((6-chloropyridin-3-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 5-(bromomethyl)-2-chloropyridine, the title compound wasobtained as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.27 (s, 1H), 8.24 (d, J=2.5 Hz, 1H), 7.74(dd, J=2.3, 8.4 Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 6.43 (dd, J=4.3, 13.7Hz, 1H), 5.15 (dt, J=4.8, 51.7 Hz, 1H), 4.60-4.70 (m, 1H), 4.15-4.18 (m,1H), 3.97-4.09 (m, 2H), 3.35-3.42 (m, 2H); LC/MS [M+H]=531.

Example 7 Synthesis of 2-(((2R, 3R, 4R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

2-(((2R, 3R, 4R,5R)-5-(6-Amino-9H-purin-9-yl)-4-fluoro-3-hydroxy-tetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid was prepared from diethyl 2-(((2R, 3R, 4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-malonateaccording to the procedure for Example 2. The title compound wasisolated as a white solid. LC/MS [M+H]=462.

Examples 8a, 8b, 8c and 8d Synthesis of ((R)-1-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-ethoxy-2-oxoethyl)phosphonicacid; ((S)-1-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-ethoxy-2-oxoethyl)phosphonicacid; ((R)-1-(((2R, 3R, 4S,5R)-5-(6-((tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-ethoxy-2-oxoethyl)phosphonicacid; and ((S)-1-(((2R, 3R, 4S,5R)-5-(6-((tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-ethoxy-2-oxoethyl)phosphonicacid

Step1:

To a solution ofN6,N6-bis-(tert-butoxycarbonyl)-2′-arabino-fluoro-2′-deoxy-3′-O-(tert-butoxycarbonyl)-2-chloro-adenosine(512 mg, 0.85 mmol) in toluene (5 mL) was added ethyl2-diazo-2-(diethoxyphosphoryl)acetate (37 mg, 1.10 mmol) and Rh₂(OAc)₄(37 mg, 0.08 mmol) under argon atmosphere. The resulting mixture wasstirred at 95° C. for 3 h before it was allowed to cool to roomtemperature. The organic volatile was removed under reduced pressure.The resulting crude was purified by silica gel column chromatography(5-100% EtOAc in hexanes) to provide ethyl 2-4(2R,3R,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(diethoxyphosphoryl)acetate(557 mg) as a mixture of diastereomers.

Step 2:

To a solution of ethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(diethoxyphosphoryl)acetate(345 mg, 0.42 mmol) in MeCN (6 mL) at −20° C. was added TMSBr (441 mL,3.34 mmol) dropwise. The resulting mixture was stirred from −20 to 0° C.over 26 h before it was quenched with H₂O (4 mL). The resulting mixturewas stirred at 0° C. for 20 h before it was quenched with NH₄OH (6 mL)and concentrated under reduced pressure. The crude residue was purifiedby preparative reversed-phase HPLC to provide the title compounds aswhite solids.

((R)-1-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-ethoxy-2-oxoethyl)phosphonicacid (diastereisomer 1):

¹H NMR (CD₃OD, 300 MHz) δ 8.54 (bs, 1H), 6.42 (dd, J=4.1, 10.1 Hz, 1H),5.09-5.31 (m, 1H), 4.55-4.74 (m, 1H), 4.37-4.53 (m, 1H), 4.27 (q, J=7.1Hz, 2H), 4.10-4.20 (m, 1H), 3.84-4.01 (m, 2H), 1.28 (t, J=6.9 Hz, 3H);LC/MS [M+H]=470.

((S)-1-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-ethoxy-2-oxoethyl)phosphonicacid (diastereisomer 2):

¹H NMR (CD₃OD, 300 MHz) 8.52 (bs, 1H), 6.42 (dd, J=4.6, 12.9 Hz, 1H),5.21 (dt, J=4.6, 52.3 Hz, 1H), 4.72 (dt, J=4.9, 13.1 Hz, 1H), 4.45 (d,J=18.4 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.10-4.20 (m, 1H), 3.85-4.01 (m,2H), 1.29 (t, J=7.0 Hz, 3H); LC/MS [M+H]=470.

((R)-1-(((2R, 3R, 4S,5R)-5-(6-((tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-ethoxy-2-oxoethyl)phosphonicacid (NHBoc diastereisomer 1):

¹H NMR (CD₃OD, 300 MHz) δ 8.93 (bs, 1H), 8.46 (bs, 1H), 6.56 (m, 1H),5.07-5.32 (m, 1H), 4.65-4.74 (m, 1H), 4.40 (d, J=23 Hz, 1H), 4.27 (q,J=6.9 Hz, 2H), 4.11-4.20 (m, 1H), 3.85-4.05 (m, 2H), 1.59 (bs, 9H),1.26-1.35 (m, 3H); LC/MS [M+H]=571.

((S)-1-(((2R, 3R, 4S,5R)-5-(6-((tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-ethoxy-2-oxoethyl)phosphonicacid (NHBoc diastereisomer 1):

¹H NMR (CD₃OD, 300 MHz) δ 8.95 (bs, 1H), 8.46 (bs, 1H), 6.53 (m, 1H),5.15-5.39 (m, 1H), 4.65-4.74 (m, 1H), 4.40 (m, 1H), 4.17-4.42 (m, 2H),4.11-4.17 (m, 1H), 3.85-3.95 (m, 2H), 1.59 (bs, 9H), 1.26-1.35 (m, 3H);LC/MS [M+H]=571.

Example 10 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-cyanobenzyl)malonicacid

Proceeding as described in Example 2 above, but substituting benzylbromide with 4-(bromomethyl)-benzonitrile the title compound wasprepared.

¹H NMR (CD₃OD, 300 MHz) δ 8.27 (s, 1H), 7.48 (s, 4H), 6.43-6.46 (m, 1H),5.09-5.26 (m, 1H), 4.63-4.69 (m, 1H), 3.97-4.17 (m, 3H), 3.42-3.49 (m,2H); LC/MS [M+H]=521.

Example 11 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonicacid

Proceeding as described in Example 2 above, but substituting benzylbromide with 3-(bromomethyl)benzonitrilethe, the title compound wasobtained as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.27 (s, 1H), 7.67 (bs, 1H), 7.57-7.60 (d, J=8Hz, 1H), 7.46-7.49 (d, J=8 Hz, 1H), 7.30-7.35 (t, J=8 Hz, 1H), 6.43-6.49(dd, J=4, 13 Hz, 1H), 5.08-5.28 (dt, J=4, 50 Hz, 1H), 4.62-4.71 (dt,J=4, 17 Hz, 1H), 4.17-4.21 (q, J=4 Hz, 1H), 4.00-4.12 (m, 2H), 3.40-3.52(m, 2H); LC/MS [M+H]=521.

Example 12 Synthesis of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethoxy)benzyl)malonate

Proceeding as described in Example 2 above, but substituting benzylbromide with 1-(bromomethyl)-4-(trifluoromethoxy)benzene, the titlecompound was isolated as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ 8.13 (bs, 1H), 7.25-7.28 (d, J=9 Hz, 2H),7.09-7.12 (d, J=8 Hz, 1H), 6.43-6.50 (dd, J=4, 16 Hz, 1H), 6.10 (bs,NH₂), 5.05-5.24 (dt, J=3, 52 Hz, 1H), 4.68-4.77 (dt, J=5, 19 Hz, 1H),4.22-4.28 (m, 4H), 3.98-4.10 (m, 3H), 3.41 (bs, 2H), 1.25-1.30 (dd, J=1,7 Hz, 6H); LC/MS [M+H]=636.

Example 13 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethoxy)benzyl)malonicacid, (R)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxy-tetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxo-2-(4-(trifluoromethoxy)-benzyl)propanoicacid and (S)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxy-tetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxo-2-(4-(trifluoromethoxy)-benzyl)propanoicacid

2-(((2R, 3R, 4S,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethoxy)benzyl)malonicacid was prepared from diethyl 2-4(2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethoxy)benzyl)-malonatevia base hydrolysis with aq. LiOH in THF according to the proceduredescribed in Example 2 as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.38 (s, 1H), 7.37-7.34 (d, J =8 Hz, 2H),7.07-7.09 (d, J=8 Hz, 2H), 6.39-6.46 (dd, J=4, 15 Hz, 1H), 5.05-5.25(dt, J=4, 52 Hz, 1H), 4.63-4.80 (m, 1H), 4.15-4.20 (m, 1H), 3.91-3.99(m, 2H), 3.37 (bs, 2H); LC/MS [M+H]=580.

A pair of diastereoisomer of mono-ethyl ester: (R)-2-(42R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxo-2-(4-(trifluoromethoxy)benzyl)propanoicacid and (S)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxy-tetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxo-2-(4-(trifluoromethoxy)benzyl)-propanoicacid was prepared from the partial hydrolysis of compound of Example 12.The title compounds were purified by reversed-phase HPLC and isolated aswhite solids.

Polar diastereomer 1: ¹H NMR (CD₃OD, 300 MHz) δ 8.30 (s, 1H), 7.36-7.38(d, J=8 Hz, 2H), 7.05-7.08 (d, J=8 Hz, 2H), 6.40-6.46 (dd, J=4, 14 Hz,1H), 5.08-5.27 (dt, J=4, 52 Hz, 1H), 4.63-4.78 (m, 1H), 4.15-4.26 (m,3H), 3.99-4.06 (m, 2H), 3.42-3.44 (m, 2H), 1.22-1.27 (t, J=7 Hz, 3H);LC/MS [M+H]=608.

Less polar diastereomer 2: ¹H NMR (CD₃OD, 300 MHz) δ 8.37 (s, 1H),7.35-7.38 (d, J=8 Hz, 2H), 7.05-7.08 (d, J=8 Hz, 2H), 6.42-6.48 (dd,J=4, 14 Hz, 1H), 5.10-5.30 (dt, J=4, 52 Hz, 1H), 4.64-4.71 (m, 1H),4.15-4.25 (m, 3H), 4.02-4.04 (d, J=4 Hz, 2H), 3.44 (s, 2H), 1.22-1.25(t, J=7 Hz, 3H); LC/MS [M+H]=608.

Example 14 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(hydroxymethyl)benzyl)malonicacid

Step1:

To a solution of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-formylbenzyl)malonicacid (200 mg, 0.23 mmol), prepared from diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonateand 4-(bromomethyl)benzaldehyde according to the procedure described forExample 2, in EtOH at 0° C. was added NaBH₄ (11 mg, 0.29 mmol). Theresulting mixture was stirred for 15 min before it was quenched with 1NHCl(aq) solution. The organic valotile was removed under reducedpressure and the aq. layer was extracted with EtOAc. The organic layerwas washed with brine, dried (Na2SO4) and concentrated. The cruderesidue was purified by silica gel column chromatography (0-20% EtOAc inhexanes) to provide the corresponding benzyl alcohol.

Step2-3:

The benzyl alcohol from the last step was converted to2-(42R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(hydroxymethyl)benzyl)malonicacid according to the procedure described for Example 2. The titlecompound was isolated as white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.29 (s, 1H), 7.26-7.29 (d, J=8 Hz, 2H),7.14-7.29 (d, J=8 Hz, 2H), 6.40-6.46 (dd, J=4, 13 Hz, 1H), 5.08-5.28(dt, J=4, 52 Hz, 1H), 4.63-4.72 (dt, J=4, 18 Hz, 1H), 4.49 (s, 2H),4.14-4.18 (q, J=4 Hz, 1H), 3.96-4.08 (m, 2H), 3.33-3.42 (m, 2H); LC/MS[M+H]=526.

Example 16 Synthesis of 2-(((2R, 3R, 4S,5R)-((1H-tetrazol-5-yl)methyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Step1:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(cyanomethyl)(103mg, 0.129 mmol) from the synthesis of Example 15 in toluene (5 mL)was added azidotrimethylsilane (234 uL, 1.8 mmol) in portions overperiod of 3 days followed by bis(tributyltin)oxide (20 uL, 0.0386 mmol),the reaction mixture was heated at 75° C. for three days before it wasconcentrated under reduced pressure. The crude was purified by silicagel column chromatography (0-4% MeOH in DCM) to provide diethyl2-4(2R,3R,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(1H-tetrazol-5-ylmethyl)malonate.

Step2:

Diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(1H-tetrazol-5-ylmethyOmalonatewas converted to the title compound as a white solid by proceeding asdescribed for Example 2 above.

¹H NMR (CD₃OD, 300 MHz) δ 8.58 (s, 1H), 6.44-6.50 (dd, J=4, 14 Hz, 1H),5.09-5.29 (dt, J=4, 52 Hz, 1H), 4.59-4.68 (dt, J=4, 17 Hz, 1H),4.19-4.22 (q, J=5 Hz, 1H), 4.10-4.12 (m, 2H), 3.83 (s, 2H); LC/MS[M+H]=488.

Example 17 Synthesis of 2-(3-(1H-tetrazol-5-yl)benzyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-azido-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonic acid; 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-azido-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonicacid; and 2-(((2R, 3R, 4S,5R)-5-(2-azido-6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonicacid

Step1:

A mixture of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluoro-tetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonate(230 mg, 0.26 mmol) (prepared as described in Example 2 above, byreacting diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonatewith 3-(bromomethyl)benzonitrile), NaN₃ (26 mg, 0.39 mmol) and NH₄Cl (18mg, 0.34 mmol) in DMF (1.5 mL) was heated at 100° C. for 5 h before itwas allowed to cool to room temperature. The crude reaction mixture wasdiluted with EtOAc and water. The aqueous layer was further extracted(2×) with EtOAc. The combined organic layer was washed with brine, dried(MgSO₄) and concentrated. The crude was purified by reversed-phase HPLCto provide diethyl 2-(3-(1H-tetrazol-5-yl)benzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)-amino)-2-azido-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluoro-tetrahydrofuran-2-yl)methoxy)malonateand diethyl 2-(((2R, 3R, 4S,5R)-5-(2-azido-6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonate.

Step2:

Diethyl 2-(3-(1H-tetrazol-5-yl)benzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-azido-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonateand diethyl 2-(((2R, 3R, 4S,5R)-5-(2-azido-6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonatewere then converted to the corresponding title compounds according tothe procedure descrcibed for Example 2.

2-(((2R, 3R, 4S,5R)-5-(6-amino-2-azido-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonicacid:

¹H NMR (CD₃OD, 300 MHz) δ 8.66 (s, 1H), 7.66 (s, 1H), 7.56-7.59 (d, J=8Hz, 1H), 7.46-7.48 (d, J=7 Hz, 1H), 7.33-7.35 (t, J=7 Hz, 1H), 6.52-6.57(dd, J=5,11 Hz, 1H), 5.17-5.38 (dt, J=5, 52 Hz, 1H), 4.64-4.75 (dt, J=4,17 Hz, 1H), 4.21-4.25 (m, 1H), 3.97-4.16 (m, 2H), 3.41-3.54 (m, 2H);LC/MS [M+H]=528.

2-(((2R, 3R, 4S,5R)-5-(2-azido-6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonicacid:

¹H NMR (CD₃OD, 300 MHz) δ 8.72 (s, 1H), 7.67 (s, 1H), 7.56-7.59 (d, J=8Hz, 1H), 7.46-7.49 (d, J=8 Hz, 1H), 7.31-7.36 (t, J=8 Hz, 1H), 6.57-6.62(dd, J=4, 13 Hz, 1H), 5.16-5.36 (dt, J=4, 52 Hz, 1H), 4.63-4.87 (dt,J=4, 17 Hz, 1H), 4.22-4.25 (m, 1H), 4.00-4.14 (m, 2H), 3.41-3.53 (m,2H), 1.60 (s, 9H); LC/MS [M+H]=628.

2-(3-(1H-tetrazol-5-yl)benzyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-azido-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid:

¹H NMR (CD₃OD, 300 MHz) δ 8.19 (bs, 1H), 7.99 (bs, 1H), 7.77-7.79 (d,J=8 Hz, 1H), 7.49-7.52 (d, J=8 Hz, 1H), 7.36-7.41 (t, J=8 Hz, 1H),6.32-6.38 (dd, J=5, 13 Hz, 1H), 5.05-5.25 (dt, J=4, 52 Hz, 1H),4.66-4.75 (dt, J=4, 18 Hz, 1H), 4.17-4.22 (m, 1H), 3.98-4.14 (m, 2H),3.45-3.57 (m, 2H); LC/MS [M+H]=564.

Example 18 Synthesis of 2-(((2S, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3-azido-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid; and 2-(((2S, 3S, 4R,5R)-3-amino-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Step1:

To a stirred suspension of chromium trioxide (2.59 g, 25.9 mmol) inCH₂Cl₂ (60 mL) was added pyridine (4.19 mL, 51.8 mmol) dropwise andfollowed by immediately addition of acetic anhydride (2.45 mL, 25.9mmol). This brown slurry was allowed to stir at room temperature for 10minutes. To this mixture was added a solution of(2R,3R,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)-tetrahydrofuran-3-ol(synthesized from 2-chloroadenosin according to the procedure reportedby Koole, L. H. et al., Acta Chemica Scandinavica, 43, 665-669, 1989)(5.95 g, 8.64 mmol) in CH₂Cl₂ (36 mL). The resulting mixture was stirredat room temperature for 18 h before it was passed through a short silicaplug using EtOAc as eluent. The filtrate was washed with EDTA (2×100 mL)and brine (100 mL). The organic layer was separated and concentrated.The residue was purified by column chromatography on silica gel to give(2R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)-dihydrofuran-3(2H)-one(4.19 g, 71% yield).

Step2:

A solution of (2R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)-dihydrofuran-3(2H)-one(4.19 g, 6.11 mmol) in a mixture of EtOH (42 mL) and water (2.1 mL) wasstirred for 20 minute at −5° C. before the addition of sodiumborohydride (324 mg, 8.55 mmol). The reaction was stirred for 5 h beforeit was carefully quenched with 1N aq. HCl until its pH reached 5. Thereaction mixture was partitioned with EtOAc (100 mL). The organic layerwas separated and washed with water (3×50 mL), brine, dried (MgSO₄) andconcentrated. The crude residue was purified by column chromatography onsilica gel to give (2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxy-phenyl)diphenylmethoxy)methyl)tetrahydrofuran-3-ol(2.19 g, 52% yield).

Step3:

To a solution of (2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxy-phenyl)diphenylmethoxy)methyl)-tetrahydrofuran-3-ol(2.19 g, 3.18 mmol) in CH₂Cl₂ (33mL) at 0° C. under argon atmosphere wasadded pyridine (2.3 mL, 28.6 mmol) and 4-dimethylaminopyridine (1.13 g,9.22 mmol). The reaction mixture was stirred for 15 minutes beforeaddition of Tf₂O (0.803 mL, 4.77 mmol). The reaction was stirred at 0°C. for 15 minutes before it was allowed to warm up to ambienttemperature and stirred further for 4 hours. The reaction mixture wasquenched by addition of water (22 mL). The organic layer was separated,dried (MgSO₄) and concentrated. The crude residue was purified by columnchromatography on silica gel to give (2R, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)tetrahydrofuran-3-yltrifluoromethanesulfonate (2.00 g, 76% yield).

Step4:

To a solution of (2R, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)-tetrahydrofuran-3-yltrifluoromethanesulfonate (1.65 g, 2.01 mmol) in DMF (33 mL) at 0° C.was carefully added sodium azide (1.31 g, 20.1 mmol). The reaction wasallowed to warm to ambient temperature and stirred for 6 hours before itwas partitioned with EtOAc (100 mL). The organic layer was separated,washed with water (2×22 mL), brine, dried over MgSO₄ and concentrated.To the crude oil in THF (5 mL) was added Boc₂O (1.70 g, 7.64 mmol) and4-DMAP (24 mg, 0.20 mmol). The reaction was stirred under argon for 13 hbefore it was concentrated and the crude residue was purified by columnchromatography on SiO₂ to give tert-butyl (tert-butoxycarbonyl)(9-((2R,3R, 4R,5S)-4-azido-3-((tert-butyldimethylsilyl)oxy)-5-(((4-methoxyphenyl)diphenylmethoxy)methyl)-tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(1.19 g, 65% yield for 2 steps).

Step5:

To a solution of tert-butyl (tert-butoxycarbonyl)(9-((2R, 3R, 4R,5S)-4-azido-3-((tert-butyldimethylsilyl)oxy)-5-(((4-methoxyphenyl)diphenylmethoxy)methyl)-tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(1.19 g, 1.30 mmol) was in DCM (30 mL) under argon atmosphere at roomtemperature was added trifluoroacetic acid (0.483 mL, 6.50 mmol)dropwise. The reaction was stirred for 7 h before it was concentrated.The crude residue was purified by column chromatography on SiO₂ to givetert-butyl (tert-butoxycarbonyl)(9-((2R, 3R, 4R,5S)-4-azido-3-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(548 mg, 69% yield).

Step6:

A mixture of tert-butyl (tert-butoxycarbonyl)(9-((2R, 3R, 4R,5S)-4-azido-3-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(385 mg, 0.60 mmol) and diethyl 2-diazomalonate (145 mg, 0.78 mmol) werecharged into a 25 mL round bottom flask and azeotroped twice withtoluene. The resulting oil was dissolved in toluene (3.9 mL) andfollowed by addition of rhodium(II) acetate dimer (27 mg, 0.06) mmolunder argon atmosphere. The reaction mixture was heated at 75° C. for 3h before it was concentrated. The crude residue was purified by columnchromatography on SiO₂ to give diethyl 2-(((2S, 3R, 4R,5R)-3-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-tetrahydrofuran-2-yl)methoxy)malonate(234 mg, 48% yield).

Step7:

To a solution of diethyl 2-(((2S, 3R, 4R,5R)-3-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-tetrahydrofuran-2-yl)methoxy)malonate(234 mg, 0.29 mmol) in DMF (2.3 mL) at 0° C. was added oven dried cesiumcarbonate (191 mg, 0.59 mmol). The resulting suspension was stirred for30 minutes and followed by dropwise addition of benzyl bromide (70 μL,0.59 mmol). The reaction was allowed to warm to ambient temperature andstirred for 14 h before it was partitioned between EtOAc (25 mL) andwater (22 mL). The organic layer was separated and washed water (22 mL),brine, dried over magnesium sulfate and concentrated. The crude residuewas purified by column chromatography on SiO₂ to give diethyl 2-(((2S,3R, 4R, 5R)-3-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(100 mg, 38% yield).

Step8:

A solution of diethyl 2-(((2S, 3R, 4R,5R)-3-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(100 mg, 0.11 mmol) in EtOAc (2.0 mL) was purged three times with argongas and followed by addition of Lindlar catalyst (15 mg, 15% by wt)under a blanket of argon gas. The reaction mixture was then purged(thrice) and stirred under 1 atmosphere of H₂ for 18 h. The reactionmixture was filtered through celite and rinsed with DCM (10 mL). Thefiltrate was concentrated to provide diethyl 2-(((2S, 3R, 4R, 5R)-3-amino-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)-amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(92 mg, 94% yield) which was used in the next step without furtherpurification.

Step9:

To a solution of diethyl 2-(((2S, 3R, 4R,5R)-3-amino-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)-amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(92 mg, 0.11 mmol) in a mixture of DCM (2.3 mL) and water (92 μL) andfollowed by dropwise addition of TFA (0.92 mL). The reaction was stirredfor 16 hours before it was evaporated to dryness and azeotroped withacetonitrile twice. The resulting oil was taken up in THF (1.5 mL) and4M NaOH (106 μL, 0.42 mmol) was added at room temperature. The reactionwas stirred after 10 h before it was concentrated to dryness. The cruderesidue was purified by reversed-phase HPLC to give 2-(((2S, 3S, 4R,5R)-3-amino-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid.

¹H NMR (CD₃OD, 300 MHz) δ 8.35 (s, 1H), 7.10-7.77 (m, 5H), 6.45-6.52(dd, J=4, 10 Hz, 1H), 5.18-5.39 (dt, J=4.5, 52 Hz, 1H), 4.65-4.73 (dt,J=5, 17 Hz, 1H), 4.21-4.24 (m, 1H), 3.95-4.18 (m, 2H), 3.45-3.59 (m,2H); LC/MS [M+H]=493.

Step10:

2-(((2S, 3S, 4R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-3-azido-4-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid was prepared from diethyl 2-(((2S, 3R, 4R,5R)-3-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-tetrahydrofuran-2-yl)methoxy)malonateunder the similar deprotection conditions described in Step 9.

¹H NMR (CD₃OD, 300 MHz) δ 8.87 (bs, 1H), 6.03 (d, J=6.4Hz, 1H),5.17-5.21 (t, J=5.6 Hz, 1H), 4.61 (bs, 1H), 4.50 (bs, 1H), 4.20 (bs,1H), 3.81-3.91 (q, J=0 Hz, 2H); LC/MS [M+H]=429.

Example 19 Synthesis of 2-(((2R, 3S, 4R,5R)-4-amino-5-(6-amino-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonic acid

Step1:

To a cooled (−70° C.) solution of oxalyl chloride (4.18 mL, 48.78 mmol)in dry dichloromethane (100 mL) under argon atmosphere was added asolution of dry DMSO (7.1 mL, 99.44 mmol) in dichloromethane (18 mL)dropwise. After stirring for 30 minutes, a solution of(6aR,8R,9R,9aS)-8-(6-amino-2-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol(10.21 g, 18.76 mmol), synthesized from 2-chloroadenosine according tothe procedure reported by Secrist, John A., III et al.; (Journal ofMedicinal Chemistry, 31, 405-10, 1988); and by Chen, Robert H. K. (U.S.Pat. No. 5,208,327), in a mixture of dichloromethane and THF (46 mL,1:1/v:v) was added dropwise over a period of 30 minutes and followed bytriethylamine (16 mL, 114.44 mmol) via a syringe. The cooling bath wasremoved and the mixture was stirred at room temperature for 1.5 h beforechloroform (190 mL) and water (650 mL) were added and the pH of themixture was adjusted to neutral with 2N aq. HCl solution. The organiclayer was separated and the aqueous phase was further extracted withchloroform (2×190 mL). The combined organic phase was dried (MgSO₄) andfiltered through a short plug of celite. The filtrate was concentratedto provide(6aR,8R,9aR)-8-(6-amino-2-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9(6aH)-oneas a solid (8.37 g) which was used without further purification in thenext step.

Step2:

To a suspension of NaBH₄ (2.51 g, 66.4 mmol) in dry THF (130 mL) underargon atmosphere at 0° C. was added glacial acetic acid (19.3 mL, 337mmol) dropwise. The reaction mixture was stirred for 1.5 h and followedby addition of a solution of(6aR,8R,9aR)-8-(6-amino-2-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9(6aH)-one(3 g, 5.53 mmol) in tetrahydrofuran (30 mL) via a syringe. The mixturewas stirred for 4 h at 0° C. The organic valotile was removed underreduced pressure and the residue was partitioned with EtOAc (115 mL) andsaturated aqueous sodium bicarbonate (115 mL). The organic phase wasseparated and the aqueous layer was further extracted with EtOAc (2×100mL). The combined organic phase was dried (MgSO₄), filtered andconcentrated to provide(6aR,8R,9R,9aS)-8-(6-amino-2-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-olas a foam (2.69 g).

Step3:

To a solution of(6aR,8R,9R,9aS)-8-(6-amino-2-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol(2.297 g, 4.22 mmol) in anhydrous dichloromethane (90 mL) under argonatmosphere was added pyridine (3.1 mL, 38 mmol) and4-dimethylaminopyridine (1.5 g, 12.24 mmol). The mixture was cooled to0° C. and stirred for 15 minutes and followed by addition oftrifluoromethanesulfonic anhydride (1.1 mL, 6.33 mmol) dropwise. Afterstirring for 5 minutes, the cooling bath was removed and the mixture wasstirred at room temperature for 3 hours. The reaction was quenched withcold water (90 mL). The organic phase was separated and the aqueousphase was further extracted with DCM (2×80 mL). The combined organicphase was dried (MgSO₄), filtered and concentrated. The crude residuewas purified by column chromatography on silica gel (25-85% EtOAc inhexanes) to provide(6aR,8R,9S,9aR)-8-(6-amino-2-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]-trioxadisilocin-9-yltrifluoromethanesulfonate as a white solid (1.9 g).

Step4:

To a solution of(6aR,8R,9S,9aR)-8-(6-amino-2-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yltrifluoromethanesulfonate (1.9 g, 2.8 mmol) in anhydrous DMF (12 mL)under argon atmosphere was added sodium azide (1.83 g, 28.1 mmol). Themixture was stirred for 24 hours before it was partitioned with EtOAc(120 mL) and brine (120 mL). The organic phase was separated and theaqueous phase was further extracted with EtOAc (2×100 mL). The combinedorganic phase was dried (MgSO₄), filtered and concentrated to provide9-((6aR, 8R, 9R,9aS)-9-azido-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-2-chloro-9H-purin-6-amineas a solid (1.48 g).

Step5:

To a solution of9-((6aR,8R,9R,9aS)-9-azido-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-2-chloro-9H-purin-6-amine(1.48 g, 2.59 mmol) in anhydrous THF (31 mL) under argon atmosphere wasadded 4-dimethylaminopyridine (153 mg, 1.25 mmol) and then di-tert-butyldicarbonate (1.2 g, 5.5 mmol). The mixture was stirred at roomtemperature for 16 hours before it was partitioned with EtOAc (40 mL)and brine (60 mL). The organic phase was separated and the aqueous phasewas further extracted with EtOAc (2×40 mL). The combined organic phasewas dried (MgSO₄), filtered and concentrated. The crude product waspurified by column chromatography on silica gel (15% EtOAc in hexanes)to provide tert-butyl(tert-butoxycarbonyl)(9-((6aR,8R,9R,9aS)-9-azido-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-2-chloro-9H-purin-6-yl)di-carbamateas a viscous oil (1.857 g).

Step6:

To a solution of tert-butyl(tert-butoxycarbonyl)(9-((6aR,8R,9R,9aS)-9-azido-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-2-chloro-9H-purin-6-yl)di-carbamate(1.85 g, 2.41 mmol) in anhydrous THF (13 mL) under argon atmosphere at0° C. was added a solution of tetrabutylammonium fluoride (6.3 mL, 1.0 Min THF, 6.3 mmol) dropwise. The flask was stirred overnight at 6° C.before it was partitioned with EtOAc (50 mL) and brine (50 mL). Theorganic phase was separated and the aqueous phase was further extractedwith EtOAc (2×40 mL). The combined organic phase was dried (MgSO₄),filtered and concentrated. The crude product was purified by columnchromatography on silica gel (55% EtOAc in hexanes) to providetert-butyl(tert-butoxycarbonyl)(9-((2R,3R,4S,5R)-3-azido-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamateas a solid (1.117 g).

Step7:

To a solution of tert-butyl (tert-butoxycarbonyl)(9-((2R, 3R, 4S,5R)-3-azido-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(408 mg, 0.77 mmol) and Rh₂(OAc)₄ (14 mg, 0.04 mmol) in dry toluene (2mL) under argon atmosphere at room temperature was added diethyl2-diazomalonate (173 mg, 0.93 mmol). The resulting mixture was stirredat 75° C. for 3 hours before it was allowed to cool to ambienttemperature. The reaction mixture was then partitioned with EtOAc (20mL) and brine (20 mL). The organic phase was separated and the aqueousphase was further extracted with EtOAc (2×20 mL). The combined organicphases was dried (MgSO₄), filtered and concentrated. The residue waspurified by preparative thin layer chromatographic plates eluting with60% EtOAc in hexanes to provide diethyl 2-4(2R, 3S, 4R,5R)-4-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)malonateas a viscous oil (167 mg).

Step8:

To a solution of diethyl 2-(((2R, 3S, 4R,5R)-4-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate(167 mg, 0.24 mmol) in dry DMF (1.5 mL) under argon atmosphere was addedcesium carbonate (119 mg, 0.37 mmol) and then benzyl bromide (44 mg,0.26 mmol). Additional amount of Cs₂CO₃ (60 mg) and BnBr (40 mg) wereadded to the reaction over 1.5 h and stirred for addition 1 h. Thereaction mixture was then partitioned with EtOAc (20 mL) and brine (20mL). The organic phase was separated and the aqueous phase was furtherextracted with EtOAc (2×20 mL). The combined organic phase was dried(MgSO₄), filtered and concentrated. The residue was purified bypreparative thin layer chromatography (eluting with 40% EtOAc inhexanes) to provide diethyl 2-4(2R, 3S,4R,5R)-4-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonateas a viscous oil.

Step9:

To a solution of diethyl 2-(((2R, 3S, 4R,5R)-4-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(101 mg, 0.13 mmol) in ethanol (4 mL) was added Lindlar's catalyst (25mg) and then stirred under 1 atmosphere of H₂ for 18 hours. The reactionmixture was filtered through a plug of celite and rinsed with methanol.The filtrate was concentrated to provide diethyl 2-(((2R, 3S, 4R,5R)-4-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonateas the product (100 mg).

Step10:

To a solution of diethyl 2-(((2R, 3S, 4R,5R)-4-azido-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(100 mg, 0.13 mmol) in THF (1.5 mL) and water (0.75 mL) was addedlithium hydroxide mono-hydrate (65 mg, 1.56 mmol). The material wasvigorously stirred for 5 hours at ambient temperature and then stirredfor 66 hours at 6° C. before it was cooled to 0° C. and followed byadded a solution of 1N aq. HCl (1.7 mL). The reaction mixture wasconcentrated to provide an off-white powder (66 mg). This material wasthen taken up in a solution of trifluoroacetic acid in dichloromethane(1.5 mL, 1:1/v:v) and stirred for 1 h before it was concentrated. Theresidue was taken up in dichloromethane (5×5 mL) and concentrated eachtime. The crude was purified by reversed-phase HPLC to provide 2-(((2R,3S, 4R,5R)-4-amino-5-(6-amino-2-chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid (18 mg) as a solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.29 (s, 1H), 7.26-7.16 (m, 5H), 6.36 (d, J=9Hz, 1H), 4.6 (d, J=5 Hz, 1H), 4.53-4.47 (m, 1H), 4.43 (bs, 1H), 4.01(dd, J=2, 11 Hz, 1H), 3.80 (dd, J=2, 10 Hz, 2H), 3.46 (bs, 2H); LC/MS[M+H]=493.

Example 21 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(4-(benzylamino)-1H-benzo[d]imidazol-1-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-carboxybenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with methyl 3-(bromomethyl)benzoate, the title compound wasisolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.31 (s, 1H), 7.99 (s, 1H), 7.81-7.84 (d, J=7Hz, 1H), 7.52-7.55 (d, J=7 Hz, 1H), 7.25-7.30 (t, J=8 Hz, 1H), 6.40-6.46(dd, J=4, 13 Hz, 1H), 5.07-5.27 (dt, J=4, 52 Hz, 1H), 4.66-4.73 (dt,J=5, 17 Hz, 1H), 4.16-4.20 (m, 1H), 3.99-4.11 (m, 2H), 3.40-3.55 (m,2H); LC/MS [M+H]=540.

Example 22 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-fluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3-fluorobenzyl bromide, the title compound was isolated asa white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.33 (s, 1H), 7.03-7.18 (m, 3H), 6.81-6.82 (m,1H), 6.41-6.47 (dd, J=4, 13 Hz, 1H), 5.09-5.29 (dt, J=4, 52 Hz, 1H),4.65-4.74 (dt, J=5, 18 Hz, 1H), 4.15-4.19 (q, J=4 Hz, 1H), 3.96-4.10 (m,2H), 3.36-3.46 (m, 2H); LC/MS [M+H]=514.

Example 23 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-fluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-fluorobenzyl bromide, the title compound was isolated asa white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.33 (s, 1H), 7.26-7.30 (m, 2H), 6.81-6.87 (t,J=9 Hz, 2H), 6.41-6.47 (dd, J=4, 13 Hz, 1H), 5.09-5.29 (dt, J=4, 52 Hz,1H), 4.65-4.74 (dt, J=5, 18 Hz, 1H), 4.14-4.20 (m, 1H), 3.95-4.09 (m,2H), 3.33-3.45 (m, 2H); LC/MS [M+H]=514.

Example 24 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-methoxybenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3-methoxybenzyl bromide, the title compound was isolated asa white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.41 (s, 1H), 7.01-7.06 (t, J=7 Hz, 1H),6.83-6.85 (m, 2H), 6.64-6.66 (d, J=8 Hz, 1H), 6.42-6.48 (dd, J=4, 11 Hz,1H), 5.11-5.31 (dt, J=4, 52 Hz, 1H), 4.67-4.74 (dt, J=5, 18 Hz, 1H),4.16-4.20 (m, 1H), 3.94-4.10 (m, 2H), 3.60 (d, J=1 Hz, 3H), 3.31-3.44(m, 2H); LC/MS [M+H]=526.

Example 25 Synthesis of 2-(3-(1H-tetrazol-5-yl)benzyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Step1:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluoro-tetrahydrofuran-2-yl)methoxy)-2-(3-cyanobenzyl)malonate,prepared from diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonatewith 3-(bromomethyl)benzonitrile according to the procedure for Example2, (380mg, 0.43 mmol) in toluene (8 mL) was added azidotrimethylsilane(350 uL, 2.64 mmol) and bis(tributyltin)oxide (66 uL, 0.13 mmol) inportions over period of 4 days. The reaction mixture was then heated at75° C. for four days before it was concentrated under reduced pressure.The crude residue was purified by column chromatography silica gel (0-4%MeOH in DCM) to provide diethyl2-(((2R,3R,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluoro-tetrahydrofuran-2-yl)methoxy)-2-(3-1-H-tetrazol-5-ylbenzyl)malonate.

Step2:

Diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluoro-tetrahydrofuran-2-yl)methoxy)-2-(3-1-H-tetrazol-5-ylbenzyl)malonatewas then converted to the title compound as described in Example 2above.

¹H NMR (CD₃OD, 300 MHz) δ 8.26 (s, 1H), 7.99 (s, 1H), 7.77-7.79 (d, J=7Hz, 1H), 7.47-7.50 (d, J=8 Hz, 1H), 7.38 (t, J=7 Hz, 1H), 6.35-6.46 (m,1H), 5.06-5.27 (m, 1H), 4.66-4.80 (m, 1H), 4.20-4.21 (m, 1H), 4.00-4.17(m, 2H), 3.44-3.62 (m, 2H); LC/MS [M+H]=564.

Example 26 Synthesis of 2-(4-(1H-tetrazol-5-yl)benzyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonic acid

The title compound was prepared as described in Example 25 above bysubstituting 3-(bromomethyl)benzonitrile with4-(bromomethyl)benzonitrile,the title compound was isolated as a whitesolid.

¹H NMR (CD₃OD, 300 MHz) δ 8.27 (s, 1H), 7.79-7.82 (d, J=8 Hz, 2H),7.50-7.52 (d, J=8 Hz, 2H), 6.42-6.47 (dd, J=4, 13 Hz, 1H), 5.09-5.29(dt, J=4, 53 Hz, 1H), 4.65-4.74 (dt, J=4, 17 Hz, 1H), 4.18-4.21 (m, 1H),3.98-4.14 (m, 2H), 3.46-3.58 (m, 2H); LC/MS [M+H]=564.

Example 27 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(benzyloxy)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 1-(benzyloxy)-4-(chloromethyl)benzene, the title compoundwas isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.33 (s, 1H), 7.27-7.35 (m, 5H), 7.17-7.20 (d,J=8 Hz, 2H), 6.72-6.75 (d, J=9 Hz, 2H), 6.40-6.46 (dd, J=5, 12 Hz, 1H),5.10-5.29 (dt, J=4, 52 Hz, 1H), 4.89 (s, 2H), 4.66-4.75 (dt, J=5, 18 Hz,1H), 4.15-4.17 (m, 1H), 3.93-4.08 (m, 2H), 3.30-3.41 (dd, J=5, 14 Hz,2H); LC/MS [M+H]=602.

Example 28 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-hydroxybenzyl)malonicacid

To a solution of -(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(benzyloxy)benzyl)malonicacid (Example 27) (280 mg) in EtOAc (10 mL) was added Pd/C (50 mg, 10%wt.). The resulting mixture was stirred under 1 atmosphere of H₂ for 1.5h before it was filtered off. The filtrate was concentrated to providethe title compound as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.33-8.34 (d, J=2 Hz, 1H), 7.09-7.12 (d, J=9Hz, 2H), 6.58-6.61 (d, J=8 Hz, 2H), 6.40-6.46 (dd, J=4, 14 Hz, 1H),5.05-5.27 (dt, J=4, 52 Hz, 1H), 4.63-4.71 (dt, J=4, 33 Hz, 1H),4.14-4.18 (q, J=5 Hz, 1H), 3.96-4.00 (m, 2H), 3.46 (bs, 2H); LC/MS[M+H]=512.

Example 29 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-hydroxybenzyl)malonicacid

Proceeding as described in Examples 2 and 28 above, but substitutingbenzyl bromide with 1-(benzyloxy)-3-(chloromethyl)benzene, the titlecompound was isolated as white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.37 (s, 1H), 6.94-6.99 (t, J=8 Hz, 1H),6.76-6.78 (m, 2H), 6.56-6.59 (d, J=8 Hz, 1H), 6.41-6.46 (dd, J=3, 12 Hz,1H), 5.08-5.27 (dt, J=4, 52 Hz, 1H), 4.66-4.73 (m, 1H), 4.11-4.20 (m,1H), 3.92-4.07 (m, 2H), 3.35 (m, 2H); LC/MS [M+H]=512.

Example 30 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxy-2-fluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with methyl 4-(bromomethyl)-3-fluorobenzoate, the title compoundwas isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.25 (s, 1H), 7.51-7.60 (m, 3H), 6.38-6.44(dd, J=4, 14 Hz, 1H), 5.05-5.25 (dt, J=5, 52 Hz, 1H), 4.62-4.70 (m, 1H),4.12-4.16 (m, 1H), 3.95-4.05 (m, 2H), 3.54 (bs, 2H); LC/MS [M+H]=558.

Example 31 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxy-3-fluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with methyl 4-(bromomethyl)-2-fluorobenzoate, the title compoundwas isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.32 (bs, 1H), 7.69-7.74 (t, J=8 Hz, 1H),7.12-7.16 (m, 2H), 6.41-6.47 (dd, J=5, 14 Hz, 1H), 5.06-5.28 (dt, J=5,52 Hz, 1H), 4.65-4.73 (m, 1H), 4.14-4.19 (m, 1H), 3.92-4.04 (m, 2H),3.44 (bs, 2H); LC/MS [M+H]=558.

Example 32 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((5-(trifluoromethyl)furan-2-yl)methyl)-malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 2-(bromomethyl)-5-(trifluoromethyl)furan, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.38 (s, 1H), 6.78-6.79 (m, 4H), 6.39-6.45 (m,2H), 5.06-5.26 (dt, J=4, 53 Hz, 1H), 4.62-4.71 (dt, J=4, 17 Hz, 1H),4.13-4.16 (m, 1H), 3.97-4.00 (m, 2H), 3.58 (bs, 2H); LC/MS [M+H]=554.

Example 33 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 5-(bromomethyl)-2-(trifluoromethyl)pyridine, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.60 (bs, 1H), 8.37 (s, 1H), 7.89 (d, J=9 Hz,1H), 7.60 (d, J=8 Hz, 1H), 6.51-6.59 (dd, J=2, 22 Hz, 1H), 5.08-5.27(dt, J=4, 53 Hz, 1H), 4.62-4.71 (dt, J=5, 17 Hz, 1H), 4.21-4.24 (m, 1H),3.96-4.17 (m, 2H), 3.45-3.59 (q, J=15 Hz, 2H); LC/MS [M+H]=565.

Example 34 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-fluoro-4-(trifluoromethyl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene, thetitle compound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.76 (s, 1H), 7.27-7.49 (m, 3H), 6.51-6.56(dd, J=4, 10 Hz, 1H), 5.18-5.39 (dt, J=5, 52 Hz, 1H), 4.62-4.71 (dt,J=5, 17 Hz, 1H), 4.21-4.24 (m, 1H), 3.96-4.17 (m, 2H), 3.45-3.59 (q,J=15 Hz, 2H); LC/MS [M+H]=582.

Example 35 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((3-phenylisoxazol-5-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 5-(bromomethyl)-3-phenylisoxazole, the title compound wasisolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.96 (s, 1H), 7.40-7.80 (m, 5H), 6.51-6.56(dd, J=4, 10 Hz, 1H), 6.29 (s, 1H), 5.18-5.39 (dt, J=5, 52 Hz, 1H),4.60-4.69 (dt, J=5, 17 Hz, 1H), 4.21-4.24 (m, 1H), 3.98-4.19 (m, 2H),3.45-3.59 (q, J=15 Hz, 2H); LC/MS [M+H]=563.

Example 36 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((1-benzyl-1H-pyrazol-4-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 1-benzyl-4-(bromomethyl)-1H-pyrazole, the title compoundwas isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.45 (s, 1H), 7.56 (s, 1H), 7.414 (s, 1H),7.17-7.23 (m, 3H), 7.00-7.03 (m, 2H), 6.39-6.45 (dd, J=4, 12 Hz, 1H),5.10-5.31 (m, 3H), 4.65-4.75 (dt, J=5, 18 Hz, 1H), 4.14-4.17 (q, J=5 Hz,1H), 3.93-4.02 (m, 2H), 3.30-3.36 (m, 2H); LC/MS [M+H]=576.

Example 37 Synthesis of 2-((1H-pyrazol-4-yl)methyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

2-((1H-pyrazol-4-yl)methyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid was prepared from Example 36 (200 mg) via de-benzylation with Pd/C(50 mg, 10 wt %) in an mixture of EtOH (0.5 mL) and EtOAc (5 mL) under 1atmosphere of H₂. The catalyst was filtered off after 1 h and thefiltrate was concentrated to provide the title compound as a whitesolid.

¹H NMR (CD₃OD, 300 MHz) δ 8.46 (s, 1H), 7.55 (s, 2H), 6.44-6.49 (dd,J=5, 12 Hz, 1H), 5.12-5.31 (dt, J=4, 53 Hz, 1H), 4.68-4.74 (dt, J=5, 13Hz, 1H), 4.17-4.22 (q, J=5 Hz, 1H), 3.96-4.03 (m, 2H), 3.36 (bs, 2H);LC/MS [M+H]=486.

Example 38 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2-carboxythiazol-5-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with methyl 4-(bromomethyl)thiazole-2-carboxylate, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.38 (d, J=2 Hz, 1H), 7.37-7.59 (d, J=4 Hz,1H), 6.41-6.48 (m, 1H), 5.05-5.25 (dt, J=3, 52 Hz, 1H), 4.65-4.74 (m,1H), 4.22-4.24 (m, 1H), 3.98 (bs, 2H), 3.66 (bs, 2H); LC/MS [M+H]=548.

Example 39 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2-carboxythiazol-4-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with methyl 5-(bromomethyl)thiazole-2-carboxylate, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.48 (bs, 1H), 7.64 (bs, 1H), 6.41-6.44 (dd,J=5, 8 Hz, 1H), 5.14-5.33 (dt, J=4, 52 Hz, 1H), 4.73-4.79 (m, 1H),4.01-4.04 (m, 1H), 3.70-3.79 (m, 2H), 3.73 (bs, 2H); LC/MS [M+H]=547

Example 40 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((5-carboxy-l-methyl-1H-pyrazol-3-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with ethyl 5-(bromomethyl)-1-methyl-1H-pyrazole-3-carboxylate,the title compound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.90 (bs, 1H), 6.51-6.56 (dd, J=4, 10 Hz, 1H),6.35 (s, 1H), 5.19-5.40 (dt, J=4.7, 52 Hz, 1H), 4.61-4.70 (dt, J=5, 17Hz, 1H), 4.21-4.24 (m, 1H), 3.96-4.17 (m, 2H), 3.93 (s, 3H), 3.45-3.59(q, J=15 Hz, 2H); LC/MS [M+H]=543.

Example 41 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((3-carboxyisoxazol-5-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with ethyl 5-(bromomethyl)isoxazole-3-carboxylate, tThe titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.98 (bs, 1H), 6.51-6.56 (dd, J=4, 10 Hz, 1H),6.39 (s, 1H), 5.18-5.39 (dt, J=5, 52 Hz, 1H), 4.62-4.71 (dt, J=5, 17 Hz,1H), 4.21-4.25 (m, 1H), 3.97-4.17 (m, 2H), 3.43-3.56 (q, J=15 Hz, 2H);LC/MS [M+H]=531.

Example 42 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-cyano-3-fluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-(bromomethyl)-2-fluorobenzonitrile, the title compoundwas isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.35 (bs, 1H), 7.04-7.57 (m, 3H), 6.48-6.54(dd, J=4, 10 Hz, 1H), 5.18-5.39 (dt, J=5, 52 Hz, 1H), 4.65-4.75 (dt,J=5, 17 Hz, 1H), 4.21-4.24 (m, 1H), 3.94-4.18 (m, 2H), 3.45-3.60 (m,2H); LC/MS [M+H]=539.

Example 43 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((5-carboxythiophen-3-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with ethyl 4-(bromomethyl)thiophene-2-carboxylate, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.40 (bs, 1H), 7.73 (s, 1H), 7.50 (s, 1H),6.44-6.49 (dd, J=3, 11 Hz, 1H), 5.03-5.30 (m, 1H), 4.65-4.75 (m, 1H),4.15-4.23 (m, 1H), 3.96-4.10 (m, 2H), 3.39-3.53 (m, 2H); LC/MS[M+H]=546.

Example 44 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((5-carboxythiophen-2-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with ethyl 5-(bromomethyl)thiophene-2-carboxylate, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.36 (s, 1H), 7.52-7.53 (d, J=4 Hz, 1H),6.99-7.00 (d, J=4 Hz, 1H), 6.41-6.47 (dd, J=4, 14 Hz, 1H), 5.07-5.26(dt, J=3, 48 Hz, 1H), 4.68-4.76 (dt, J=4, 18 Hz, 1H), 4.18-4.21 (m, 1H),4.01-4.11 (m, 2H), 3.66 (s, 2H); LC/MS [M+H]=546.

Example 45 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(carboxymethyl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with ethyl 2-(4-(bromomethyl)phenyl)acetate., the title compoundwas isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.32 (bs, 1H), 7.24-7.26 (d, J=8 Hz, 2H),7.08-7.10 (d, J=8 Hz, 2H), 6.40-6.46 (dd, J=4, 13 Hz, 1H), 5.07-5.27(dt, J=4, 53 Hz, 1H), 4.63-4.72 (dt, J=4, 18 Hz, 1H), 4.15-4.20 (m, 1H),3.95-4.06 (m, 2H), 3.44-3.54 (m, 2H), 3.40 (bs, 2H); LC/MS [M+H]=554.

Example 46 Synthesis of 2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid; (R)-2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-methoxy-3-oxopropanoicacid; (S)-2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-methoxy-3-oxopropanoicacid; (R)-2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxopropanoicacid; and (S)-2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxopropanoicacid

Step1:

Diethyl 2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R, 3R,4S,5R)-5-(6-N-(bis-(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(200 mg, 0.22 mmol), prepared by alkylatingN6,N6-bis-(tert-butoxycarbonyl)-2′-arabino-fluoro-2′-deoxy-3′-O-(tert-butoxycarbonyl)-2-chloro-adenosinewith 4-phenylbenzyl bromide according to the procedure described forExample 2, was dissolved in DCM (5 mL) and followed by addition of TFA(1.5 mL) at room temperature. The resulting mixture was stirred for 7 hbefore it was concentrated. The residue was re-taken up in DCM (3×5 mL)and concentrated under reduced pressure each time to remove theexcessive TFA to provide diethyl 2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R,3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate.

Step2:

To a solution of diethyl 2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(0.22 mmol) in a mixture of MeOH (2 mL), THF (2 mL) and H₂O (2 mL) wasadded LiOH.H₂O (90 mg, 2.15 mmol). The resulting mixture was stirred atroom temperature for 5 h before the organic volatiles were removed underreduced pressure. The residue was re-dissolved in H₂O (2 mL) andacidified with 1N aq.HCl solution to pH 5 before it was concentratedunder reduced pressure. The crude residue was purified by reversed-phaseHPLC to provide the title compounds as white solids.

2-([1,1′-Biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid:

¹H NMR (CD₃OD, 300 MHz) δ 8.34 (bs, 1H), 7.27-7.46 (m, 9H), 6.41-6.46(dd, J=5, 12 Hz, 1H), 5.09-5.30 (dt, J=4, 52 Hz, 1H), 4.68-4.77 (dt,J=4, 18 Hz, 1H), 4.15-4.19 (m, 1H), 3.97-4.12 (m, 2H), 3.43-3.52 (m,2H); LC/MS [M+H]=572.

2-([1,1′-Biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-methoxy-3-oxopropanoicacid (Methyl diastereomer 1):

¹H NMR (CD₃OD, 300 MHz) δ 8.31 (bs, 1H), 7.26-7.48 (m, 9H), 6.42-6.47(dd, J=5, 12 Hz, 1H), 5.10-5.31 (dt, J=4, 52 Hz, 1H), 4.67-4.77 (dt,J=5, 18 Hz, 1H), 4.15-4.19 (m, 1H), 3.98-4.10 (m, 2H), 3.78 (s, 3H),3.40-3.52 (m, 2H); LC/MS [M+H]=586.

2-([1,1′-B iphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-methoxy-3-oxopropanoicacid (Methyl diastereomer 2):

¹H NMR (CD₃OD, 300 MHz) δ 8.31 (bs, 1H), 7.25-7.47 (m, 9H), 6.40-6.46(dd, J=4, 12 Hz, 1H), 5.10-5.30 (dt, J=4, 53 Hz, 1H), 4.66-4.76 (dt,J=5, 18 Hz, 1H), 4.08-4.17 (m, 2H), 3.92-3.96 (m, 1H), 3.79 (s, 3H),3.40-3.52 (m, 2H); LC/MS [M+H]=586.

2-([1,1′-Biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxopropanoicacid (Ethyl diastereomer 1):

¹H NMR (CD₃OD, 300 MHz) δ 8.33 (bs, 1H), 7.26-7.48 (m, 9H), 6.44-6.49(dd, J=5, 8 Hz, 1H), 5.11-5.31 (dt, J=4, 53 Hz, 1H), 4.71-4.77 (m, 1H),4.17-4.25 (m, 3H), 4.00-4.09 (m, 2H), 3.44 (bs, 2H), 1.24-1.28 (t, J=7Hz, 3H); LC/MS [M+H]=600.

2-([1,1′-Biphenyl]-4-ylmethyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxopropanoicacid (Ethyl diastereomer 2):

¹H NMR (CD₃OD, 300 MHz) δ 8.31 (bs, 1H), 7.25-7.47 (m, 9H), 6.40-6.46(dd, J=5, 12 Hz, 1H), 5.10-5.30 (dt, J=4, 52 Hz, 1H), 4.68-4.77 (dt,J=5, 18 Hz, 1H), 4.22-4.29 (q, J=7 Hz, 2H), 4.10-4.19 (m, 2H), 3.93-3.98(m, 1H), 3.40-3.53 (m, 2H), 1.25-1.30 (t, J=7 Hz, 3H); LC/MS [M+H]=600.

Example 47 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-chloro-4-methoxybenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-(bromomethyl)-2-chloro-1-methoxybenzene, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.34 (bs, 1H), 7.27-7.28 (d, J=2 Hz, 1H),7.27-7.28 (dd, J=2, 8 Hz, 1H), 6.77-6.80 (d, J=8 Hz, 1H), 6.43-6.48 (dd,J=4, 11 Hz, 1H), 5.11-5.31 (dt, J=4, 52 Hz, 1H), 4.69-4.83 (dt, J=5, 17Hz, 1H), 4.15-4.20 (m, 1H), 3.93-4.10 (m, 2H), 3.75 (s, 3H), 3.27-3.34(m, 2H); LC/MS [M+H]=560.

Example 48 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-sulfamoylbenzyl)malonic acid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-(bromomethyl)benzenesulfonamide, the title compound wasisolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.27 (s, 1H), 7.70-7.73 (d, J=8 Hz, 2H),7.47-7.49 (d, J=8 Hz, 2H), 6.40-6.46 (dd, J=4, 14 Hz, 1H), 5.07-5.27(dt, J=4, 52 Hz, 1H), 4.62-4.70 (dt, J=5, 17 Hz, 1H), 4.16-4.20 (q, J=5Hz, 1H), 3.99-4.10 (m, 2H), 3.34-3.52 (m, 2H); LC/MS [M+H]=575.

Example 49 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-chloro-2-fluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-chloro-2-fluorobenzyl bromide, the title compound wasisolated as a white solid. [M+H]=548.

Example 50 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-((2-carboxyethyl)carbamoyl)-benzyl)malonicacid

Diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(4-((3-methoxy-3-oxopropyl)carbamoyl)-benzyl)malonatewas prepared as described in Example 2 above but substituting benzylbromide with methyl 3-(4-(bromomethyl)benzamido)propanoate. The titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.25 (s, 1H), 7.59-7.62 (d, J=8 Hz, 2H),7.37-7.40 (d, J=8 Hz, 1H), 6.40-6.46 (dd, J=5, 14 Hz, 1H), 5.07-5.27(dt, J=4, 52 Hz, 1H), 4.62-4.71 (dt, J=4, 18 Hz, 1H), 4.14-4.19 (m, 1H),3.97-4.10 (m, 2H), 3.57-3.62 (t, J=7 Hz, 2H), 3.42-3.52 (m, 2H),2.59-2.64 (t, J=7 Hz, 3H); LC/MS [M+H]=611.

Example 51 Synthesis of -(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2-carboxybenzofuran-5-yl)methyl)-malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with methyl 5-(bromomethyl)benzofuran-2-carboxylate, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.21 (s, 1H), 7.64-7.67 (d, J=9 Hz, 2H), 7.59(s, 1H), 7.39-7.42 (dd, J=1, 9 Hz, 1H), 7.14 (s, 1H), 6.45-6.49 (dd,J=7, 7 Hz, 1H), 5.16-5.38 (dt, J=6, 53 Hz, 1H), 4.75-4.85 (m, 1H),4.18-4.25 (m, 2H), 3.88-3.93 (dd, J=3, 10 Hz, 2H), 3.45-3.64 (m, 2H);LC/MS [M+H]=580.

Example 52 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2,2,2-trifluoroethoxy)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 1-(bromomethyl)-4-(2,2,2-trifluoroethoxy)benzene, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.31 (s, 1H), 7.23-7.26 (d, J=9 Hz, 2H),6.76-6.79 (d, J=8 Hz, 2H), 6.40-6.46 (dd, J=4, 13 Hz, 1H), 5.08-5.28(dt, J=4, 52 Hz, 1H), 4.65-4.73 (dt, J=4, 17 Hz, 1H), 4.33-4.43 (m, 2H),4.14-4.19 (m, 1H), 3.95-4.08 (m, 2H), 3.32-3.42 (m, 2H); LC/MS[M+H]=594.

Example 53 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(carboxymethoxy)benzyl)malonicacid

Step1:

Diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(cyanomethoxy)benzyl)malonatewas prepared according to the procedure described in Example 2 above butsubstituting benzyl bromide with 2-(4-(bromomethyl)phenoxy)acetonitrile.

Step2:

Diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(cyanomethoxy)benzyl)malonatewas then hydrolyzed to the corresponding acid with the treatment of aq.LiOH in THF. The title compound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.31 (s, 1H), 7.20-7.23 (d, J=8 Hz, 2H),6.71-6.74 (d, J=8 Hz, 2H), 6.40-6.46 (dd, J=4, 13 Hz, 1H), 5.07-5.27(dt, J=4, 52 Hz, 1H), 4.65-4.73 (m, 1H), 4.55 (s, 2H), 4.13-4.18 (m,1H), 3.95-4.05 (m, 2H), 3.35-3.42 (m, 2H); LC/MS [M+H]=570.

Example 54 Synthesis of2-benzyl-2-(((2R,3R,4S,5R)-5-(2-chloro-6-hydroxy-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Step1:

To a solution of ((2R, 3R, 4S,5R)-3-(benzoyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methylbenzoate (2.00 g, 3.77 mmol) in DMF was added K₂CO₃ (625 mg, 4.52 mmol)and 1-pentanol (6554, 6.03 mmol). The resulting mixture was stirred at40° C. for 2 h before it was allowed to cool to room temperature anddiluted with EtOAc and water. The organic layer was separated, washedwith brine, dried (MgSO4) and concentrated. This crude was dissolved inMeOH (20 mL) and cooled to 0° C. To this mixture was added a solution ofNH₃ in MeOH (19 mL, 2.0 M in MeOH). The reaction mixture was stirredfrom 0° C. to ambient temperature over 18 h before it was concentratedunder reduced pressure. The crude was purified by SiO₂ columnchromatography (0-5% MeOH in DCM) to provide (2R, 3R, 4S,5R)-5-(2-chloro-6-(pentyloxy)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol.

Step2-4:

(2R, 3R, 4S,5R)-5-(2-chloro-6-(pentyloxy)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-olwas then converted to diethyl 2-(((2R, 3R, 4S,5R)-3-((tert-butoxycarbonyl)oxy)-5-(2-chloro-6-(pentyloxy)-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methoxy)malonateaccording to the procedure described for Example 1.

Step5:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-3-((tert-butoxycarbonyl)oxy)-5-(2-chloro-6-(pentyloxy)-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(210 mg, 0.29 mmol) in DCM (4 mL) at room temperature was added TFA (2.0mL). The reaction mixture was then stirred for 8 h before it wasconcentrated under reduced pressure. The residue was re-dissolved in DCM(2×5 mL) and re-concentrated. The crude product was dissolved in amixture of THF (3 mL) and water (3 mL) and followed by addition ofLiOH.H₂O (139 mg). The reaction was then stirred at room temperature for48 h before it was concentrated under reduced pressure. The residue wasre-dissolved in water (2 mL) and acidified to pH 6 with 1N aq. HClsolution before it was concentrated. The crude residue was purified byreversed-phase HPLC to provide the title compound as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.25 (s, 1H), 7.16-7.30 (m, 5H), 6.38-6.45(dd, J=4, 15 Hz, 1H), 5.05-5.25 (dt, J=4, 52 Hz, 1H), 4.59-4.68 (dt,J=5, 17 Hz, 1H), 4.15-4.19 (q, J=5 Hz, 1H), 3.96-4.05 (m, 2H), 3.40 (bs,2H); LC/MS [M+H]=497.

Example 55 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 2-(4-(bromomethyl)phenyl)-5-methyl-1,3,4-oxadiazole, thetitle compound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.26 (s, 1H), 7.66-7.69 (d, J=8 Hz, 2H),7.37-7.39 (d, J=8 Hz, 2H), 6.42-6.47 (dd, J=5, 9 Hz, 1H), 5.14-5.33 (dt,J=4, 53 Hz, 1H), 4.62-4.70 (dt, J=5, 19 Hz, 1H), 4.15-4.20 (m, 2H),3.92-3.96 (m, 1H), 3.32-3.52 (q, J=15 Hz, 2H), 2.61 (s, 3H); LC/MS[M+H]=578.

Example 56 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2′-cyano-[1,1′-biphenyl]-4-yl)-methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.41 (d, J=1 Hz, 1H), 7.70-7.73 (dd, J=1, 8Hz, 1H), 7.55-7.58 (dd, J=1, 8 Hz, 1H), 7.29-7.49 (m, 6H), 6.41-6.46(dd, J=5, 11 Hz, 1H), 5.12-5.33 (dt, J=5, 53 Hz, 1H), 4.69-4.79 (dt,J=5, 18 Hz, 1H), 4.10-4.21 (m, 2H), 3.98-4.02 (m, 1H), 3.47-3.59 (m,2H); LC/MS [M+H]=597.

Example 57 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((5-chlorobenzo[b]thiophen-3-yl)methyl)-malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3-(bromomethyl)-5-chlorobenzo[b]thiophene, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.43 (s, 1H), 7.80 (s, 1H), 7.48-7.53 (m, 2H),6.99-7.02 (d, J=8 Hz, 1H), 6.44-6.49 (dd, J=5, 10 Hz, 1H), 5.16-5.34 (m,1H), 4.72-4.82 (dt, J=6, 18 Hz, 1H), 4.12-4.20 (m, 2H), 3.94-3.98 (m,1H), 3.57-3.71 (m, 2H); LC/MS [M+H]=586.

Example 58 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(benzo[d]thiazol-2-ylmethyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 2-(bromomethyl)benzo[d]thiazole, the title compound wasisolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.35 (s, 1H), 7.80-7.86 (m, 2H), 7.28-7.41 (m,2H), 6.37-6.42 (dd, J=4.5, 13 Hz, 1H), 5.08-5.11 (dt, J=4, 52 Hz, 1H),4.72-4.81 (dt, J=4, 17 Hz, 1H), 4.08-4.19 (m, 3H), 3.99 (s, 2H); LC/MS[M+H]=553.

Example 59 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methylcarbamoyl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-(bromomethyl)-N-methylbenzamide, the title compound wasisolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.26 (s, 1H), 7.59-7.62 (d, J=8 Hz, 2H),7.37-7.40 (d, J=8 Hz, 2H), 6.40-6.46 (dd, J=4, 13 Hz, 1H), 5.07-5.27(dt, J=4, 52 Hz, 1H), 4.62-4.71 (dt, J=5, 18 Hz, 1H), 4.17-4.18 (q, J=4Hz, 3H), 3.97-4.10 (m, 2H), 3.42-3.52 (m, 2H); LC/MS [M+H]=553.

Example 60 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonicacid

Step1:

Dibenzyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonatewas prepared by proceeding as described in Example 1 above by, utilizingdibenzyl diazomalonate instead of diethyl diazomalonate.

Step2:

Proceeding as described in Example 2 above, but utilizing methyl4-(bromomethyl)benzoate in place of benzyl bromide and subsequentremoval of Boc groups with treatment of TFA provided dibenzyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxy-tetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)-malonate.

Steps 3-4:

The title compound was isolated as a white solid from dibenzyl 2-(((2R,3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxy-tetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonateaccording to the procedure described for Example 28.

¹H NMR (CD₃OD, 300 MHz) δ 8.27 (s, 1H), 7.69-7.71 (d, J=8 Hz, 2H),7.36-7.38 (d, J=8 Hz, 2H), 6.42-6.47 (dd, J=5, 11 Hz, 1H), 5.11-5.31(dt, J=5, 53 Hz, 1H), 4.68-4.77 (dt, J=5, 18 Hz, 1H), 3.94-4.18 (m, 3H),3.42-3.55 (m, 2H), 3.42-3.52 (m, 2H); LC/MS [M+H]=554.

Example 61 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-((E)-2-carboxyvinyl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with methyl 3-(4-bromomethyl)cinnamate, the title compound wasisolated as a white solid. LC/MS [M+H]=566.

Example 62 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-carboxyethyl)benzyl)malonicacid

The title compound was prepared from2-(42R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-((E)-2-carboxyvinyl)benzyl)malonicacid (Example 58) by reducing the olefin bond with Pd/C in EtOH under 1atmosphere of H₂. The title compound isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.38 (s, 1H), 8.30 (bs, 1H), 7.00-7.24 (m,5H), 6.38-6.41 (dd, J=4, 10 Hz, 1H), 5.07-5.26 (dt, J=4.7, 52 Hz, 1H),3.98-4.16 (m, 4H), 3.98-4.20 (m, 2H), 3.32-3.36 (m, 4H), 2.52-2.85 (m,5H); LC/MS [M+H]=534.2.

Example 63 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-phenoxybenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3-(phenoxy)benzyl bromide, the title compound was preparedand isolated as a a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.38 (bs, 1H), 7.02-7.22 (m, 6H), 6.70-6.81(m, 3H), 6.37-6.41 (dd, J=4.3, 13 Hz, 1H), 5.07-5.25 (m, 1H), 4.62-4.67(m, 1H), 3.93-4.18 (m, 3H), 3.24 (m, 2H); LC/MS [M+H]=589.

Example 64 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3-trifluoromethoxybenzyl bromide, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.34 (bs, 1H), 7.20-7.29 (m, 3H), 7.01-7.04(d, 1H), 6.42-6.48 (dd, J=4, 13 Hz, 1H), 5.08-5.28 (dt, J=4.7, 52 Hz,1H), 4.62-4.71 (dt, J=5, 17 Hz, 1H), 4.15-4.19 (m, 1H), 3.98-4.10 (m,2H), 3.44-3.45 (m, 2H); LC/MS [M+H]=580.8.

Example 65 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethyl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3-trifluoromethylbenzyl bromide, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.96 (bs, 1H), 7.37-7.59 (m, 4H), 6.51-6.56(dd, J=4, 10 Hz, 1H), 5.18-5.39 (dt, J=4.7, 52 Hz, 1H), 4.62-4.71 (dt,J=5, 17 Hz, 1H), 4.21-4.24 (m, 1H), 3.96-4.17 (m, 2H), 3.45-3.59 (q,J=15 Hz, 2H); LC/MS [M+H]=564.8.

Example 66 Synthesis of2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(naphthalen-2-ylmethyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with naphthalene-2-ylmethyl bromide, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.29 (bs, 1H), 7.60-7.72 (m, 3H), 7.51-7.53(d, J=8 Hz, 1H), 7.36-7.39 (d, J=8 Hz, 1H), 7.19-7.30 (m, 2H), 6.40-6.45(dd, J=4.7, 10.6 Hz, 1H), 5.10-5.30 (dt, J=4.3, 53 Hz, 1H), 4.71-4.77(m, 1H), 4.09-4.20 (m, 1H), 3.91-4.12 (m, 2H), 3.49-3.62 (q, J=11 Hz,2H); LC/MS [M+H]=546.9.

Example 67 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethyl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-trifluoromethylbenzyl bromide, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.31 (d, J=1.6 Hz, 1H), 7.41-7.49 (m, 4H),6.40-6.46 (dd, J=4.3, 13.4 Hz, 1H), 5.08-5.29 (dt, J=4.0, 52 Hz, 1H),4.63-4.88 (dt, J=3.9, 17.5 Hz, 1H), 4.15-4.19 (m, 1H), 3.99-4.10 (m,2H), 3.49 (m, 2H); LC/MS [M+H]=564.8.

Example 68 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methylsulfonyl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-methylsulfonylbenzyl bromide, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.28 (d, J=1 Hz, 1H), 7.55-7.75 (dd, J=8.3, 50Hz, 2H), 6.40-6.46 (dd, J=4.6, 13.3 Hz, 1H), 5.08-5.26 (dt, J=4.1, 52Hz, 1H), 4.63-4.68 (dt, J=4.9, 17.6 Hz, 1H), 4.15-4.19 (m, 1H),3.99-4.10 (m, 2H), 3.52-3.53 (m, 2H), 3.03 (s, 3H); LC/MS [M+H]=574.9.

Example 69 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(dimethylcarbamoyl)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3-(bromomethyl)-N,N-dimethylbenzamide, the title compoundwas prepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.42 (bs, 1H), 7.20-7.41 (m, 4H), 6.41-6.47(dd, J=4.4, 13.3 Hz, 1H), 5.08-5.28 (dt, J=4, 52 Hz, 1H), 4.59-4.68 (dt,J=4.3, 17.6 Hz, 1H), 4.14-4.19 (q, J=5 Hz, 1H), 4.02-4.05 (m, 2H),3.52-3.53 (m, 2H), 3.00 (s, 3H), 2.92 (s, 3H); LC/MS [M+H]=568.

Example 70 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(thiophen-3-ylmethyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3-(bromomethyl)thiophene, the title compound was preparedand isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.38 (bs, 1H), 7.19-7.22 (m, 2H), 7.02-7.04(m, 1H), 6.40-6.46 (dd, J=4.3, 13.4 Hz, 1H), 5.07-5.27 (dt, J=3.9, 9, 52Hz, 1H), 4.60-4.66 (m, 1H), 4.15-4.19 (q, J=5 Hz, 1H), 3.94-3.99 (m,2H), 3.45 (bs, 2H); LC/MS [M+H]=503.

Example 71 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-aminobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with tert-butyl (3-(bromomethyl)phenyl)carbamate, the titlecompound was prepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.33 (bs, 1H), 7.09-7.25 (bs, 4H), 6.39-6.44(d, J=15 Hz, 1H), 5.06-5.24 (m, 1H), 4.18-4.28 (d, J=18.4 Hz, 1H), 4.20(bs, 1H), 3.90 (bs, 2H), 3.39 (s, 2H); LC/MS [M+H]=512.

Example 72 Synthesis of 2-benzyl-2-(((2R, 3R, 4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Step1:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(benzyl(tert-butoxycarbonyl)-amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluoro-tetrahydrofuran-2-yl)methoxy)malonate(130 mg, 0.173 mmol) in DMF (2 mL) at 25° C. was added Cs₂CO₃ (113 mg,0.346 mmol). The reaction mixture was stirred for 30 min and followed byaddition of benzyl bromide (41 uL, 0.346 mmol). The reaction mixture wasstirred for 3.5 h before it was diluted with H₂O (15 mL) and extractedwith EtOAc. The combined organic layer was washed further with H₂O,brine, dried over Na₂SO₄ and concentrated. The resulting crude waspurified by silica gel column chromatography (0-20% EtOAc in hexanes) toprovide diethyl 2-benzyl-2-(((2R, 3R, 4S,5R)-5-(6-(benzyl(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonateas a foam.

Diethyl 2-benzyl-2-(((2R, 3R, 4S,5R)-5-(6-(benzyl(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonatewas converted into the title compound according to the proceduredescribed for Example 2.

¹H NMR (CD₃OD, 300 MHz) δ 8.23 (bs, 1H), 7.23-7.42 (m, 10H), 6.36-6.45(dd, J=2.6, 22.6 Hz, 1H), 4.96-5.14 (dd, J=2.4, 50 Hz, 1H), 4.74-4.80(m, 3H), 4.16-4.19 (m, 1H), 3.73-3.88 (m, 2H), 3.35-3.40 (m, 2H); LC/MS[M+H]=587.

Example 73 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-hydroxybutyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with (4-bromobutoxy)(tert-butyl)dimethylsilane, the titlecompound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.50-8.54 (m, 1H), 6.41-6.47 (dd, J=4.6, 12.7Hz, 1H), 5.17-5.36 (dt, J=4.3, 52 Hz, 1H), 4.18-4.28 (dt, J=4.2, 17.3Hz, 1H), 4.08-4.17 (m, 2H), 3.70-3.90 (m, 2H), 3.52 (t, J=6.3 Hz, 1H),2.12-2.18 (m, 2H), 1.35-1.72 (m, 4H); LC/MS [M+H]=479.

Example 74 Synthesis of 1-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)ethane-1,1,2-tricarboxylicacid

Proceeding as described in Example 2 above but substituting benzylbromide with (ethyl 2-bromoacetate, the title compound was isolated as awhite solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.78 (bs, 1H), 6.44-6.49 (dd, J=4.6, 11.8 Hz,1H), 5.12-5.32 (dt, J=4.5, 52 Hz, 1H), 4.67-4.76 (m, 1H), 4.13-4.18 (q,J=4.7 Hz, 1H), 3.93-3.99 (m, 2H), 3.23 (s, 2H); LC/MS [M+H]=464.

Example 75 Synthesis of2-(((2R,3R,4S,5R)-5-(4-(benzylamino)-1H-benzo[dlimidazol-1-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Step1:

A suspension ofN6,N6-bis-Boc-5′-O-tert-butyldiphenylsilyl-3′-O-Boc-2-chloro-adenosine(1.00 g, 1.19 mol) in a mixture of t-BuOH and H₂O (8 mL, 1:1/v:v) wasrefluxed for 13 h before it was allowed to cool to room temperature andconcentrated. The crude residue was purified by silica gel columnchromatography (5-20% EtOAc in hexanes) to provide tert-butyl(9-((2R,3S,4R,5R)-4-((tert-butoxycarbonyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydro-furan-2-yl)-2-chloro-9H-purin-6-yl)carbamate.

Step2:

To a solution tert-butyl(9-((2R,3S,4R,5R)-4-((tert-butoxycarbonyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(500 mg, 0.67 mmol) in MeCN (4 mL) at room temperature was added DBU(201 uL, 1.35 mmol) and followed by BnBr (119 uL, 0.996 mmol). Thereaction mixture was stirred for 3 h before it was diluted with EtOAc(10 mL) and H₂O (10 mL). The organic layer was separated, washed withbrine, dried over Na₂SO₄ and concentrated. The crude residue waspurified by silica gel column chromatography (0-15% EtOAc in hexanes) toprovide tert-butyl benzyl (9-((2R, 3S, 4R,5R)-4-((tert-butoxycarbonyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)-methyl)-3-fluorotetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate.

Step3:

To a solution of tert-butyl benzyl (9-((2R, 3S, 4R,5R)-4-((tert-butoxycarbonyl)-oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(545 mg, 0.655 mmol) was dissolved in THF (1 mL) at 0° C. and followedby addition of a solution of TBAF (1 mL, 0.982 mmol, 1 M in THF)dropwise. The reaction mixture was stirred from 0° C. to roomtemperature over 2.5 h before it was evaporated to dryness. The residuewas purified by silica gel column chromatography (0-20% EtOAc inhexanes) to provide tert-butyl benzyl (9-((2R, 3S, 4R,5R)-4-((tert-butoxycarbonyl)oxy)-3-fluoro-5-(hydroxymethyl)tetrahydro-furan-2-yl)-2-chloro-9H-purin-6-yl)carbamate.

Step4:

To a solution of tert-butyl benzyl (9-((2R, 3S, 4R,5R)-4-((tert-butoxycarbonyl)-oxy)-3-fluoro-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(300 mg, 0.505 mmol) in toluene (3 mL) was added diethyl 2-diazomalonate(122 mg, 0.657 mmol) and Rh₂(OAc)₄ (22 mg, 0.051 mmol) under argonatmosphere. The resulting mixture was stirred at 80° C. for 2.5 h beforeit was allowed to cool to room temperature. The organic volatile wasremoved under reduced pressure. The resulting crude was purified bysilica gel column chromatography (0-25% EtOAc in hexanes) to providediethyl 2-4(2R,3R,4S,5R)-5-(6-(benzyl(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate.

Step5:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(benzyl(tert-butoxycarbonyl)-amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydro-furan-2-yl)methoxy)malonate(200 mg, 0.27 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added TFA (3 mL). Theresulting mixture was warm up to room temperature and stirred for 2 hbefore it was concentrated under reduced pressure to provide crudediethyl 2-4(2R, 3R, 4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonateas a TFA salt which was used in the next step without furtherpurification.

Step6:

To a solution of crude diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonateTFA salt (0.27 mmol) in THF (3 mL) and H₂O (1 mL) at room temperaturewas added LiOH monohydrate (50 mg). The resulting mixture was stirredovernight before it was cooled to 0° C. and acidified to pH ˜6 with 1Naq. HCl solution and concentrated under reduced pressure. The cruderesidue was purified by preparative reverse-phase HPLC to provide2-(42R,3R,4S,5R)-5-(4-(benzylamino)-1H-benzo[d]imidazol-1-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.40 (bs, 1H), 7.26-7.42 (m, 5H), 6.40-6.47(dd, J=4.5, 13.8 Hz, 1H), 5.07-5.28 (dt, J=3.9, 52 Hz, 1H), 4.77 (bs,2H), 4.62-4.70 (m, 2H), 4.13-4.16 (q, J=5 Hz, 1H), 3.90-3.98 (m, 2H);LC/MS [M+H]=497.

Example 76 Synthesis of ((R)-1-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(methylamino)-2-oxoethyl)phosphonicacid; and ((S)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(methylamino)-2-oxoethyl)phosphonicacid

Step1:

To a solution of diastereomeric mixture (1:1 ratio) of methyl 2-(((2R,3R, 4S,5R)-5-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)-oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(dimethoxyphosphoryl)acetate(0.352 mmol) in THF (4 mL) at room temperature was added a solution of1N aq. LiOH (0.7 mL). The resulting mixture was stirred for 75 minutesbefore it was cooled to 0° C. and acidified to pH ˜6 with 1N aq. HClsolution and concentrated under reduced pressure to provide a crudediastereomeric mixture of 2-(((2R, 3R, 4S,5R)-5-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluoro-tetrahydrofuran-2-yl)methoxy)-2-(dimethoxyphosphoryl)aceticacid (280 mg) which was used in the next step without furtherpurification.

Step2:

To a solution of the above crude diastereomeric mixture of2-(((2R,3R,4S,5R)-5-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(dimethoxyphosphoryl)aceticacid (140 mg, 0.182 mmol) in dry DCM (10 mL) was added methylaminehydrochloride (49 mg, 0.73 mmol) and HATU (140 mg, 0.364 mmol). To thismixture was added DIEA (0.22 mL, 1.3 mmol) and the reaction mixture wasstirred overnight. Additional amounts of methylamine (25 mg), HATU (140mg) and DIEA (0.22 mL) were added and the mixture was stirred for 20hours before it was quenched with water (25 mL). The organic layer wasseparated and the aqueous was extracted with DCM (3×25 mL). The combinedorganic phases were dried and the crude product was purified viapreparative TLC (60% ethyl acetate/hexane) to provide methyl 2-(((2R,3R, 4S,5R)-5-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(diethoxyphosphoryl)acetamide(66 mg) as a mixture of diastereomers (1:1 ratio).

Step3:

Diastereomeric mixture of methyl 2-(((2R, 3R, 4S,5R)-5-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(diethoxyphosphoryl)acetamidewas converted to a diastereomeric mixture of ((R)-1-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(methylamino)-2-oxoethyl)phosphonicacid and ((S)-1-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(methylamino)-2-oxoethyl)phosphonicacid as a solid (1:1 ratio) according to the procedure for Examples 8aand 8b.

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (1:1 ratio): δ8.63-8.91 (m, 1H), 6.51 (d, 1H, diastereomeric), 5.11-5.40 (m, 1H),4.18-4.70 (m, 3H), 4.01 (broad s, 2H), 2.78 (broad d, 3H); LC/MS[M+H]=456.

Example 77 Synthesis of 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid

2-(((2R, 3S, 4R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid was prepared according to the procedure described for Examples 1and 2. Isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.42 (bs, 1H), 7.79-7.82 (d, J=8.2 Hz, 2H),7.34-7.37 (d, J=8.2 Hz, 2H), 6.02-6.04 (d, J=6.2 Hz, 1H), 4.74-4.78 (m,1H), 4.30-4.35 (m, 2H), 3.80-4.04 (ddd, J=3, 10, 59 Hz, 2H), 3.52 (bs,2H); LC/MS [M+H]=538.

Example 78 Synthesis of 1-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)ethane-1,1,2-tricarboxylicacid

1-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)ethane-1,1,2-tricarboxylicacid was prepared according to the procedure described for Example 2.Isolated as a white solid.

¹H NMR (D₂O, 300 MHz) δ 8.49 (bs, 1H), 5.95-5.96 (d, J=1 Hz, 1H),4.60-4.49 (m, 1H), 4.30-4.34 (m, 2H), 3.61-3.68 (m, 2H), 2.92-2.94 (m,2H); LC/MS [M−H]=462.

Example 79 Synthesis of (S)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(1H-tetrazol-5-yl)aceticacid and (R)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(1H-tetrazol-5-yl)aceticacid

Step1:

To a solution of 2-chloro-2′,3′-O-isopropylideneadenosine (7.66 g, 22.4mmol) in DMF (70 mL) at 0° C., under argon atmosphere was addedimidazole (3.8 g, 56 mmol) and followed by TBDMSCl (4.033 g, 26.89mmol), which was added in 4 equal portions over 30 minutes. The reactionmixture was stirred for 2 hours at 0° C. and then allowed to warm up toroom temperature and stirred for 18 hours. The solvent was removed onthe rotary evaporator and the remainder was quenched with H₂O (150 mL)and extracted with EtOAc (3×150 mL). The combined organic layer waswashed further with H₂O (100 mL), brine (100 mL), dried over Na₂SO₄ andconcentrated to provide 9-((3aR, 4R, 6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-chloro-9H-purin-6-amine(10.78 g) as a white solid.

Step2:

To a solution of 9-((3aR, 4R, 6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-chloro-9H-purin-6-amine(10.2 g, 22.37 mmol) in dry DMF (150 mL) was added Et₃N (6.8 mL, 48.42mmol) and 4-DMAP (273 mg, 2.24 mmol). The mixture under argon atmospherewas cooled to 0° C. and followed by dropwise addition of a solution ofBoc₂O (10.36 g, 47.45 mmol) in dry DMF (5 mL). The reaction mixture wasstirred for 1 hour at 0° C. and then at ambient for 18 hours. Thesolvent was then removed on the rotary evaporator and the remainder waspurified by silica gel column chromatography (22-40% EtOAc in hexanes)to provideN6,N6-bis-Boc-5′-O-tert-butyldimethylsilyl-2′-3′-O-isopropylidene-2-chloro-adenosine(10.36 g) as a solid.

Step3:

N6,N6-bis-Boc-5′-O-tert-butyldimethylsilyl-2′-3′-O-isopropylidene-2-chloro-adenosine(9.66 g, 14.72 mmol) was dissolved in dry THF (80 mL) and to thismixture was added a solution of TBAF (22.1 mL, 22.1 mmol, 1 M in THF)dropwise. The reaction mixture was stirred 18 hours before it wasevaporated to dryness. The remainder was purified by silica gel columnchromatography (33-70% EtOAc in hexanes) to provideN6,N6-bis-Boc-2′-3′-O-isopropylidene-2-chloro-adenosine (7.18 g) as asolid.

Step4:

To a solution of N6,N6-bis-Boc-2′-3′-O-isopropylidene-2-chloro-adenosine(2.5 g, 4.61 mmol) in toluene (15 mL) was added ethyl cyanodiazoacetate(770 mg, 5.35 mmol) and the flask was evacuated and back filled withargon. Rh₂(OAc)₄ (41 mg, 0.09 mmol) was added and the flask was againevacuated and back-filled with argon. The resulting mixture was stirredat 90° C. for 1.5 hours and then over-night at ambient temperature.Additional amounts of ethyl cyanoacetate (200 mg, 1.44 mmol) andRh₂(OAc)4 (41 mg, 0.09 mmol) were added and the mixture was heated at90° C. for an additional 4 hours before it was allowed to cool to roomtemperature. The crude mixture was purified by silica gel columnchromatography (10-70% EtOAc in hexanes) to provide ethyl 2-(((3aR, 4R,6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-cyanoacetate(1.22 g) as a mixture of diastereomers (1:1 ratio).

Step5:

To a solution of diastereomeric mixture of ethyl 2-(((3aR, 4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-cyanoacetate(211 mg, 0.323 mmol) in dry toluene (2 mL) was addedazidotrimethylsilane (90 uL, 0.65 mmol) and bis(tributyltin) oxide (58mg, 0.097 mmol). The resulting mixture was stirred at 90° C. for 4hours. Additional azidotrimethylsilane (90 uL, 0.65 mmol) andbis(tributyltin) oxide (20 mg, 0.033 mmol) were added and the mixturewas stirred at 90° C. for 24 hours. The resultant material wasconcentrated under reduced pressure and the remainder was purified bypreparative silica gel TLC (1% MeOH in EtOAc) to provide ethyl 2-(((3aR,4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-(1H-tetrazol-5-yl)acetate(80 mg) as a mixture of diastereomers as a solid (1:1 ratio).

Step6:

To a solution of diastereomeric mixture of ethyl 2-(((3aR, 4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-(1H-tetrazol-5-yl)acetate(80 mg, 0.115 mmol) in THF (1 mL) at room temperature was added asolution of 1N aq. NaOH (0.29 mL, 0.29 mmol). The resulting mixture wasstirred for 30 minutes before it was acidified to pH ˜6 with 1N aq. HClsolution and concentrated under reduced pressure to provide 2-4(3aR, 4R,6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-(1H-tetrazol-5-yl)aceticacid as a diastereomeric mixture (1:1 ratio). This crude product wasused in the following step without further purification.

Step7:

To a solution of diastereomeric mixture of 2-(((3aR, 4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-(1H-tetrazol-5-yl)aceticacid (0.115 mmol) in CH₂Cl₂ (0.5 mL) was added TFA (0.5 mL) and H₂O (2drops). The resulting mixture was stirred for 4 hours and thenconcentrated under reduced pressure. The crude residue was purified bypreparative reverse-phase HPLC to provide a mixture of diastereomers(S)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(1H-tetrazol-5-yl)aceticacid and (R)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(1H-tetrazol-5-yl)aceticacid (25 mg) as a solid (1:1 ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (1:1 ratio) forExample 78 δ 9.27 (d, 1H, diastereomeric), 6.07-6.13 (m, 1H), 5.66-5.69(m, 1H), 4.61-4.70 (m, 1H), 4.36-4.55 (m, 1H), 4.36-4.33 (m, 1H),3.93-4.20 (m, 1H), 3.79-3.87 (m, 1H); LC/MS [M+H]=428.

Example 80 Synthesis of (S)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid;(R)-2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid; (S)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-methoxy-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid and (R)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-methoxy-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid

Step1:

To a solution of diastereomeric mixture of ethyl 2-(((3aR, 4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-cyanoacetate(1.09 g, 1.67 mmol) in DMF (7.5 mL) at 25° C. was added Cs₂CO₃ (816 mg,2.504 mmol) and BnBr (0.22 mL, 1.837 mmol). The reaction mixture wasstirred for 2 hours. Diluted brine solution (25 mL) was added and thematerial was extracted with EtOAc (3×25 mL). The combined organic layerwas washed further with brine (25 mL), dried over Na₂SO₄ andconcentrated. The resulting crude was purified by silica gel columnchromatography (5-60% EtOAc in hexanes) to provide (S)-ethyl 2-(((3aR,4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-cyano-3-phenylpropanoateand (R)-ethyl 2-4(3aR, 4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-cyano-3-phenylpropanoateas a mixture of diastereomers (ca. 1:1 ratio).

Step2:

The above diastereomeric mixture of (S)-ethyl 2-4(3aR, 4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-cyano-3-phenylpropanoateand (R)-ethyl 2-(((3aR, 4R, 6R,6aR)-6-(N6,N6-bis-Boc-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-cyano-3-phenylpropanoate(817 mg, 1.099 mmol) in dry toluene (2 mL) was addedazidotrimethylsilane (0.29 mL, 2.2 mmol) and bis(tributyltin) oxide (197mg, 0.33 mmol). The resulting mixture was stirred at 80° C. for 1 hour.Additional amounts of azidotrimethylsilane (0.29 mL, 2.2 mmol) andbis(tributyltin) oxide (50 mg, 0.08 mmol) were added and the mixture wasstirred at 80° C. for 4.5 hours. Additional azidotrimethylsilane (0.29mL, 2.2 mmol) was added and the mixture was heated further for 2.5hours. Additional azidotrimethylsilane (3×0.29 mL, 3×2.2 mmol) and wereadded and the mixture was stirred at 70-80° C. over a period of 44hours. The material was cooled to ambient temperature and the crude waspurified via preparative silica gel TLC (1% MeOH in EtOAc) to provideethyl 2-(((3aR, 4R, 6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoate(754 mg, solid) as a mixture of diastereomers (ca. 1:1 ratio).

Step3:

To a solution of diastereomeric mixture of ethyl 2-(((3aR, 4R, 6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoate(605 mg, 0.77 mmol) in CH₂Cl₂ (4 mL) was added TFA (4 mL) and H₂O (4drops). The resulting mixture was stirred for 2 hours and thenconcentrated under reduced pressure. To the residue was added CH₂Cl₂ (10mL) and the solvent was then concentrated (cycle repeated 5 times) toprovide ethyl 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoateas a mixture of diastereomers (ca. 1:1 ratio).

Step4:

To a solution of above diastereomeric mixture of ethyl 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoate(420 mg, 0.77 mmol) in MeOH (5 mL) at room temperature was added asolution of 2N aq. NaOH (1.9 mL, 3.9 mmol). The resulting mixture waswarmed to 62° C. and stirred for 16 hours. Additional 2N aq. NaOH (1.0mL, 2.0 mmol) was added. The mixture was heated to 70° C. and stirredfor 6 hours. The mixture was cooled to ambient temperature and acidifiedto pH ˜6 with 1N aq. HCl solution and concentrated under reducedpressure. The crude residue was purified by preparative reverse-phaseHPLC to provide two fractions. The first fraction eluted contained adiastereomeric mixture of (S)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid (Example 80-a) and (R)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid (Example 80-b) as a solid (ca.1:1 ratio). The second fractioneluted contained a diastereomeric mixture of (S)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-methoxy-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid (Example 80-d) and (R)-2-(((2R, 3S, 4R,5R)-5-(6-amino-2-methoxy-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid (Example 80-c) as a solid (ca.1:1 ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio)for Examples 80-a and 80-b δ 8.37 (d, 1H, diastereomeric), 7.00-7.38(m,5H), 5.92-6.04 (m, 1H), 4.67-4.81 (m, 1H), 4.35-4.46 (m, 1H), 4.16-4.30(m, 1H), 3.93-4.20 (m, 2H), 3.86-3.98 (m, 1H), 3.60-3.81 (m, 2H); LC/MS[M+H]=518.

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio)for Examples 80-c and 80-d δ 8.44 (d, 1H, diastereomeric), 7.02-7.25(m,5H), 5.97-6.05 (m, 1H), 4.71-4.83 (m, 1H), 4.37-4.51 (m, 1H), 4.21-4.32(m, 1H), 4.12 (d, 3H, diastereomeric), 3.57-3.96 (m, 4H); LC/MS[M+H]=514.

Example 82 Synthesis of 2-benzyl-2-(((2R, 3R, 4S,5R)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Step1:

2,6-Dichloro-9-(2-C-methyl-2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)purine(3.0 g, 5.65 mmol, 1 eq) in DMF (30 mL) was added K₂CO₃ (0.82 g, 5.93mmol, 1.05 eq). To the mixture was added cyclopentanethiol (582.55 mg,5.70 mmol, 610 uL, 1.01 eq) in DMF (40 mL) at 35° C. dropwise over 30min. The mixture was stirred at 35° C. for 16 hr. LCMS showed thestarting material was consumed completely. The reaction mixture wasdiluted with Ethyl acetate (100 mL) and washed with saturated aqueousNH₄Cl (50 mL), H₂O (50 mL) and brine (50 mL). The organic layer wasseparated, dried over Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The crude mixture was purified by combi-flash onsilica gel (Petroleum ether: Ethyl acetate=10:1 to 3:2) to give ((2R,3R, 4S,5R)-3-(benzoyloxy)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methylbenzoate (2.48 g, 73.5% yield) was obtained as a light yellow gum.

Step2:

A mixture of ((2R, 3R, 4S,5R)-3-(benzoyloxy)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methylbenzoate (2.28 g, 3.82 mmol, 1 eq) in a solution of saturated NH₃ inMeOH (65.06 mg, 3.82 mmol, 25 mL, 1 eq) was stirred at 0° C. for 2 h,and then at 25° C. for 16 h. The reaction mixture was concentrated invacuo an the resulting gum was dissolved in ethyl acetate (30 mL). Thesolution was washed with saturated aqueous NH₄Cl (30 mL). The aqueouslayer was extracted with ethyl acetate (3×10 mL). The organic combinedlayer was dried over Na₂SO₄, filtered and concentrated to give a lightyellow gum. The crude gum was purified by column chromatography onsilica gel to provide (2R, 3R, 4S,5R)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol(1.8 g, 88.7% yield) as a light yellow gum.

Step3:

To a solution of (2R, 3R, 4S,5R)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol(1.34 g, 3.45 mmol, 1 eq) and imidazole (563.04 mg, 8.27 mmol, 2.4 eq)in DMF (13.4 mL) was added TBDPSCl (1.14 g, 4.14 mmol, 1.06 mL, 1.2 eq)in DMF (6.7 mL) at 0° C. The reaction mixture was stirred at 20-25° C.for 16h. Additional amount of TBDPSCl (88 uL, 0.1 eq) was added to thereaction mixture and stirred at 20-25° C. for 3 h. The reaction mixturewas quenched with H₂O (70 mL). The aqueous phase was extracted withEtOAc (3×70 mL). The combined organic layer was washed with brine (100mL), dried over Na₂SO₄, filtered and concentrated. The crude waspurified by flash column chromatography on silica gel (eluted withpetroleum ether/EtOAc with gradient 1:0-4:1) to provide (2R, 3R, 4S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluorotetrahydrofuran-3-olas a white solid.

Step4:

To a solution of (2R, 3R, 4S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluorotetrahydrofuran-3-ol(1.28 g, 2.04 mmol, 1 eq) and 4-DMAP (37.40 mg, 306.10 umol, 0.15 eq) inDMF (12 mL) was added Boc₂O (668.06 mg, 3.06 mmol, 1.5 eq) and TEA(568.08 uL, 4.08 mmol, 2.0 eq) dropwise at 0° C. The reaction mixturewas stirred at 20-25° C. for lh. The mixture was washed with H₂O (50mL).The aqueous phase was extracted with EtOAc (3×30 mL). The combinedorganic layer was washed with brine (100 mL), dried over Na₂SO₄,filtered and concentrated. The crude was purified by columnchromatography on silica gel (eluted with petroleum ether/EtOAc withgradient 1:0-4:1) to provide tert-butyl ((2R, 3R,4S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluorotetrahydrofuran-3-yl)carbonate (1.4 g, 94% yield) as a white foam.

Step5:

To a solution of tert-butyl ((2R, 3R, 4S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluorotetrahydrofuran-3-yl)carbonate (1.4 g, 1.92 mmol, 1 eq) in THF (14 mL) was added TBAF in THF(1 M, 2.89 mL, 1.5 eq) dropwise at 0° C. The reaction mixture wasstirred at 0° C. for 1.5 h. before it was quenched with aq. NH₄Cl (30mL). The aqueous phase was extracted with EtOAc (3×30 mL). The combinedorganic layer was washed with brine (50 mL), dried over Na₂SO₄, filteredand concentrated. The crude was purified by column chromatography onsilica gel (eluted with petroleum ether/EtOAc with gradient 1:0-4:1) toprovide tert-butyl ((2R, 3R,4S,5R)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl)carbonate as a white foam.

Steps 6-9:

2-Benzyl-2-(((2R, 3R, 4S,5R)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid was prepared from tert-butyl((2R,3R,4S,5R)-5-(2-chloro-6-(cyclopentylthio)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl)carbonate according to the procedure described for Example 2. The titlecompound was prepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.48 (s, 1H), 7.13-7.29 (m, 5H), 6.48-6.55(dd, J=3.63 Hz, J=3.60 Hz, 1H), 5.10-5.30 (m, 1H), 4.63-4.72 (m, 1H),4.31-4.36 (m, 1H), 4.16-4.20 (m, 1H), 3.97-4,02 (m, 2H), 3.40 (s, 2H),2.29-2.37 (m, 2H), 1.73-1.86 (m, 6H); LC/MS [M+H]=581.1.

Example 83 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2,2-difluorobenzo[d][1,3]dioxo]-5-yl)methyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 5-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole, the titlecompound was prepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.34 (s, 1H), 7.14 (s, 1H), 7.02-7.04 (d,J=8.14 Hz, 1H), 6.90-6.93 (d, J=8.26 Hz, 1H), 6.44-6.49 (dd, J=4.44 Hz,J=4.29 Hz, 1H), 5.11-5.32 (dt=4.3, 52 Hz, 1H), 4.67-4.76 (m, 1H),4.10-4.19 (m, 2H), 3.95-3.99 (m, 1H), 3.36-3.49 (q, J=13.44 Hz, 2H);LC/MS [M+H]=576.

Example 84 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carbamoylbenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-(bromomethyl)benzamide, the title compound was preparedand isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.27 (s, 1H), 7.67-7.70 (d, J=8.02 Hz, 2H),7.39-7.41 (d, J=8.05 Hz, 2H), 6.39-6.45(dd, J=4.56, 14.31 Hz, 1H),5.06-5.26 (t, J=3.90, 53 Hz, 1H), 4.61-4.70 (dt, J=4.10, 17 Hz, J=4.11Hz, 1H), 4.14-4.19 (m, 1H), 3.98-4.09 (m, 2H), 3.47 (s, 2H); LC/MS[M+H]=539.

Example 85 Synthesis of 2-(((2S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid

Step1:

To a solution of (2R, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)tetrahydrofuran-3-ol (2 g, 2.91 mmol, 1 eq) in dichloroethane (20 mL)was added di(imidazol-1-yl)methanethione (776.77 mg, 4.36 mmol, 1.5 eq).The resulting mixture was warmed to 70° C. and stirred for 5 hoursbefore it was concentrated to dryness. The residue was purified by flashcolumn (SiO₂, eluted with 40% EtOAc in petroleum ether) to provide0-((2R, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)tetrahydrofuran-3-yl) 1H-imidazole-1-carbothioate (1.53 g, 66% yield) asa white solid.

Step2:

To a solution of O-((2R, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)tetrahydrofuran-3-yl) 1H-imidazole-l-carbothioate (1.63 g, 2.04 mmol, 1eq.) in toluene (15 mL) was added AIBN (67.05 mg, 408.30 umol, 0.2 eq.)under nitrogen atmosphere. The reaction was heated at 110° C. and(n-Bu)₃SnH (891.31 mg, 3.06 mmol, 810.28 uL, 1.5 eq.) was added to thereaction carefully dropwise. The reaction was stirred at 110° C. for 1hour before it was quenched with sat. KF aq. (3 mL) and the reactionmixture was concentrated to dryness. The reaction was purified by flashcolumn (SiO₂, eluted with 30% EtOAc in petroleum ether) to provide9-((2R, 3R, 5S)-3-((tert-butyldimethylsilyl)oxy)-5-(((4-methoxyphenyl)diphenylmethoxy)methyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-amine (969 mg, 71% yield) as awhite solid.

Step3:

To a solution of 9-((2R, 3R, 5S)-3-((tert-butyldimethylsilyl)oxy)-5-(((4-methoxyphenyl)diphenylmethoxy)methyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-amine (969 mg, 1.44 mmol, 1eq.) in DMF (10 mL) was added TEA (583.40 mg, 5.77 mmol, 802.48 uL, 4eq.), DMAP (35.22 mg, 288.27 umol, 0.2 eq.) and Boc₂O (1.26 g, 5.77mmol, 1.32 mL, 4 eq.). The resulting mixture was stirred at 25° C. for0.5 hour before it was diluted with H₂O (50 mL), extracted with EtOAc(20 mL×4). The combined organic layers were washed with brine (30 mL×2),dried over Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by flash column chromatography (SiO₂, eluted with 20% EtOAc inpetroleum ether) to provide the bis-N-Boc protected product (1.05 g, 83%yield) as a white solid.

Step4:

To a solution of the bis-N-Boc protected product from the previous step(1.7 g, 1.95 mmol, 1 eq.) in DCM (20 mL) was added a solution of TFA(216.39 uL, 2.92 mmol, 1.5 eq.) in DCM (20 mL) at 0° C. dropwise. Theresulting mixture was stirred at 25° C. for 1 hour. Additional 100 mg ofTFA was added to the reaction and stirred further for 6 hours at 25° C.The reaction was quenched with TEA (2 mL) and concentrated to dryness.The residue was purified by flash column chromatography (SiO₂, elutedwith 20% EtOAc in petroleum ether) to provide the desired alcohol (662mg, 51% yield) as a white solid.

Step5:

To a solution of the alcohol from the previous step (680 mg, 1.13 mmol,1 eq.) and Rh₂(OAc)₄ (25.04 mg, 113.30 umol, 0.05 eq.) in toluene (8 mL)was added a solution of diethyl 2-diazomalonate (274.20 mg, 1.47 mmol,1.3 eq.) in toluene (3 mL) dropwise at 95° C. under N2 atmosphere. Theresulting mixture was stirred at 95° C. for 5 hours before it wasconcentrated to dryness. The residue was purified by flash columnchromatography (SiO₂, eluted with 20% EtOAc in petroleum ether) toprovide diethyl2-(((2S,4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)malonate(490 mg, 54% yield) as a light yellow gum.

Step6:

To a solution of diethyl 2-(((2S, 4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)etrahydrofuran-2-yl)methoxy)malonate (300 mg, 395.61 umol, 1 eq.) in DMF(3 mL) was added K₂CO₃ (109.35 mg, 791.21 umol, 2 eq.) at 25° C. Afterstirring for 30 min, methyl 4-(bromomethyl)benzoate (181.24 mg, 791.21umol, 2 eq.) was added to the reaction mixture. The resulting mixturewas stirred at 25° C. for 4 hours to give a white suspension. LCMSshowed the reaction was completed. The reaction was diluted with H₂O (20mL), extracted with EtOAc (10 mL×3). The combined organic layers werewashed with brine (15 mL), dried over Na₂SO₄, filtered and concentratedto dryness. The residue was purified by flash column (SiO₂, eluted with20% EtOAc in petroleum ether) to provide diethyl 2-(((2S, 4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate(199.3 mg, 55% yield, 99%) as a colorless gum.

Step7:

To a solution of diethyl 2-(((2S, 4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate (168mg) in DCM (2 mL) at room temperature was added a solution of TFA (2.5mL). The resulting mixture was stirred for 4 h before H₂O (1 mL) wasadded and the reaction mixture was stirred further for 4 h. The reactionwas concentrated and azeotroped with DCM (3×10 mL) to provide the crude2-(((2S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid which was used in the subsequent step without further purification.

¹H NMR (CD₃OD, 300 MHz) δ 8.54 (s, 1H), 7.76-7.79 (d, J=8.26 Hz, 2H),7.32-7.34 (d, J=7.99 Hz, 2H), 5.96 (s, 1H), 4.63-4.70 (m, 2H), 4.09-4.12(d, J=10.27 Hz, 1H), 3.76-3.80 (d, J=10 Hz, 1H), 3.48 (s, 2H), 2.39-2.50(m, 1H), 1.98-2.03 (m, 1H); LC/MS [M+H]=522.

Example 86

Synthesis of 2-(((2S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(benzyloxy)benzyl)malonicacid

Proceeding as described in Example 85 above but substituting methyl4-(bromomethyl)benzoate with 1-(bromomethyl)-4-(phenylmethoxy)benzene,the title compound was prepared and isolated as a white solid.

¹HNMR (CD₃OD, 300 MHz) δ 8.51 (s, 1H), 7.26-7.37 (m, 5H), 7.12-7.14 (d,J=8.56 Hz, 2H), 6.71-6.74 (d, J=8.53 Hz, 2H), 5.95 (s, 1H), 4.92 (s,2H), 4.59-4.66 (m, 2H), 4.09-4.13 (d, J=10.42 Hz, 1H), 3.74-3.78 (d,J=11.23 Hz, 1H), 3.37-3.43 (m, 2H), 2.40-2.49 (m, 1H), 1.96-2.03 (m,1H); LC/MS [M+H]=584.

Example 87 Synthesis of 2-(((2R, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-(bromomethyl)benzamide, the title compound was preparedand isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.45 (s, 1H), 7.69-7.72 (d, J=8.11 Hz, 2H),7.35-7.37 (d, J=8.08 Hz, 2H), 6.21-6.26 (d, J=16.42 Hz, 1H), 4.44-4.56(dd, J=9.34, 24.5 Hz, 1H), 4.21-4.27 (m, 2H), 3.94-3.97 (d, J=8.71 Hz,1H), 3.46-3.60 (q, J=13.99 Hz, 2H), 1.08-1.15 (d, J=22.18 Hz, 3H); LC/MS[M+H]=554.

Example 88 Synthesis of 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(2H-tetrazol-5-yl)-3-(thiophen-3-yl)propanoicacid

Proceeding as described in Example 80 above but substituting benzylbromide with 3-(bromomethyl)thiophene, the title compound was preparedand isolated as a solid mixture of diastereomers (ca.3:2 ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.3:2 ratio):

Minor isomer: δ 8.42 (bs, 1H), 7.25-7.20 (m, 1H), 7.08 (bs,1H), 6.81 (d,J=4.92 Hz, 1H), 6.01 (d, J=5.64 Hz, 1H), 4.80 (t, J=5.25 Hz, 1H), 4.43(t, J=4.25 Hz, 1H), 4.31-4.22 (m, 1H), 4.0-3.88 (m, 1H), 3.82-3.68 (m,3H); LC/MS [M+H]=524.

Major isomer: δ 8.39 (bs, 1H), 7.18-7.14 (m, 1H), 7.08 (bs,1H), 6.78 (d,J=4.95 Hz, 1H), 5.98 (d, J=5.37 Hz, 1H), 4.73 (t, J=5.15 Hz, 1H), 4.36(t, J=4.31 Hz, 1H), 4.31-4.22 (m, 1H), 4.0-3.88 (m, 1H), 3.82-3.68 (m,3H); LC/MS [M+H]=524.

Example 89 Synthesis of 2-benzyl-2-(((2R, 3R, 4S,5R)-5-(2-chloro-6-(pentylthio)-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-ethoxy-3-oxopropanoicacid

Proceeding as described in Example 82 above but substitutingcyclopentanethiol with pentane-1-thiol, the title compound was preparedand isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.48-8.53 (t, J=8.16 Hz, 1H), 7.14-7.26 (m,5H), 6.49-6.55 (m, 1H), 5.10-5.32 (m, 1H), 4.65-4.73 (m, 1H), 4.17-4.23(m, 3H), 3.99-4.05 (m, 2H), 3.31-3.40 (m, 4H), 1.76-1.86 (m, 2H),1.20-1.54 (m, 7H), 0.93-0.98 (t, J=6.9 Hz, 3H); LC/MS [M+H]=611.

Example 90 Synthesis of 2-benzyl-2-(((2R, 3R, 4S,5R)-5-(2-chloro-6-(pentylthio)-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Proceeding as described in Example 2 above by treating diethyl2-benzyl-2-(((2R,3R,4S,5R)-3-((tert-butoxycarbonyl)oxy)-5-(2-chloro-6-(pentylthio)-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methoxy)malonatewith aq. LiOH in THF at room temperature to provide 2-benzyl-2-(((2R,3R, 4S,5R)-5-(2-chloro-6-(pentylthio)-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid, the title compound was isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.51 (s, 1H), 7.14-7.31 (m, 5H), 6.48-6.54(dd, J=4.20, 4.35 Hz, 1H), 5.10-5.30 (dt, J=3.86, 52 Hz, 1H), 4.64-4.73(dt, J=4.68, 17.94 Hz, 1H), 4.15-4.21 (m, 1H), 3.99-4.06 (m, 2H),3.31-3.40 (m, 4H), 1.81-1.95 (m, 2H), 1.36-1.54 (m, 4H), 0.90-0.98 (m,3H); LC/MS [M+H]=583.

Example 91 Synthesis of 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(2H-tetrazol-5-yl)-3-(4-(trifluoromethyl)phenyl)propanoic acid

Proceeding as described in Example 80 above but substituting benzylbromide with 4-(trifluoromethyl)benzyl bromide, the title compound wasprepared and isolated as a solid mixture of diastereomers (ca.1:1ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio):

Isomer 1: 8 8.39 (bs, 1H), 7.52-7.43 (m, 2H), 7.38-7.25 (m, 2H),6.03-5.94 (m, 1H), 4.80 (t, J=4.75 Hz, 1H), 4.48-4.38 (m, 1H), 4.32-4.21(m, 1H), 4.05-3.68 (m, 4H);

Isomer 2: 8 8.36 (bs, 1H), 7.52-7.43 (m, 2H), 7.38-7.25 (m,2 H),6.03-5.94 (m, 1H), 4.71 (t, J=4.61 Hz, 1H), 4.48-4.38 (m, 1H), 4.32-4.21(m, 1H), 4.05-3.68 (m, 4H); LC/MS [M+H]=586.

Example 92 Synthesis of 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-(pyridin-3-yl)-2-(1H-tetrazol-5-yl)propanoicacid

Proceeding as described in Example 80 above, but substituting benzylbromide with 3-(bromomethyl)pyridine hydrobromide, the title compoundwas prepared and isolated as a solid mixture of diastereomers (ca.1:1ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio): δ8.62-8.69 (m, 2H), 8.31-8.09 (m, 2H), 7.73-7.60 (m, 1H), 5.90-5.83 (m,1H), 4.45-4.12 (m, 2H), 3.88-3.50 (m, 5H); LC/MS [M+H]=519.

Example 93 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-chloro-3-(trifluoromethoxy)benzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-chloro-3-(trifluoromethoxy)benzyl bromide, the titlecompound was prepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.31 (bs, 1H), 7.28-7.37(m, 4H) 6.42-6.48 (dd,J=4, 10 Hz, 1H), 5.09-5.26 (dt, J=4.7, 52 Hz, 1H), 4.64-4.70 (dt, J=5,17 Hz, 1H), 4.18 (bs, 1H), 4.03 (bs, 2H), 3.41 (bs, 2H); LC/MS[M+H]=614.1.

Example 94 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-chloro-2,6-difluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-chloro-2,6-di-fluorobenzyl bromide, the title compoundwas prepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.18 (d, J=11.6 Hz, 1H), 6.88-6.96 (m, 2H),6.33-6.39 (dd, J=4, 10 Hz, 1H), 5.04-5.23 (dt, J=4.7, 52 Hz, 1H),4.55-4.65 (dt, J=5, 17 Hz, 1H), 4.25-4.31 (m, 2H), 3.93 (bs, 1H),3.43-3.59 (q, J=15 Hz, 2H); LC/MS [M+H]=566.1.

Example 95 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(2-fluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 2-fluorobenzyl bromide, the title compound was prepared andisolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.28 (s, 1H), 7.38-7.43 (m, 1H), 7.18-7.20 (m,2H), 6.96-7.03 (m, 1H), 6.37-6.44 (dd, J=4, 10 Hz, 1H), 5.04-5.24 (dt,J=4.7, 52 Hz, 1H), 4.61-4.67 (dt, J=5, 17 Hz, 1H), 4.13-4.15 (m, 1H),3.98 (bs, 2H), 3.48 (s, 2H); LC/MS [M+H]=514.1.

Example 96 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3,4-dichlorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 3,4-di-chlorobenzyl bromide, the title compound wasprepared and isolated as a white solid.

¹HNMR (CD₃OD, 300 MHz) δ 8.32 (s, 1H), 7.43 (bs, 1H), 7.15-7.28 (m, 2H),6.42-6.48 (dd, J=4, 10 Hz, 1H), 5.09-5.29 (dt, J=4.7, 52 Hz, 1H),4.65-4.73 (dt, J=5, 17 Hz, 1H), 4.13-4.22 (m, 1H), 3.97-4.05 (m, 2H),3.50 (s, 2H): LC/MS [M+H]=564.1.

Example 97 Synthesis of 1-benzyl 3-(2-morpholinoethyl) 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonate

Step1:

Under an atmosphere of argon gas, mono-benzyl malonate (1.78 g, 9.17mmol) was dissolved in anhydrous DMF (11 mL) and cooled in a 0° C. bath.Potassium carbonate (317 mg, 2.29 mmol, 0.25 eq.) was added and allowedto stir for 5 minutes before addition of 4-(2-chloroethyl) morpholine(3.58 g, 19.3 mmol, 2.1 eq.). The resulting mixture was stirred at roomtemperature for 10 hours. The reaction was diluted with EtOAc (50 mL)and washed with water (2×40 mL) and brine (60 mL). The organic layer wasconcentrated and purified by silica gel column chromatography to givebenzyl (2-morpholinoethyl) malonate (1.57 g, 55% yield).

Step2:

Under an atmosphere of argon gas, a solution of benzyl(2-morpholinoethyl) malonate (1.57 g, 5.11 mmol) was dissolved inacetonitrile (16 mL) and triethylamine (1.42 mL, 10.22 mmol, 2.0 eq.)and cooled in a −10° C. bath for 15 minutes. A solution of4-acetamidobenzesulfonyl azide (1.84 g, 7.67 mmol, 1.5 eq.) inacetonitrile (16 mL) was added at a rate of 4 mL/min. The reaction wasmonitored by TLC and completed in 4 hours. The reaction was concentratedand purified by silica gel column chromatography to give 1-benzyl3-(2-morpholinoethyl) 2-diazomalonate (844 mg, 50% yield).

Step3:

(2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-yltert-butyl carbonate (1.27 g, 2.11 mmol) and 1-benzyl3-(2-morpholinoethyl) 2-diazomalonate (844 mg, 2.53 mmol, 1.2 eq.) werecharged into a 25 mL round-bottom flask and azeotroped twice withtoluene. The resulting oil was dissolved in toluene (13 mL) under anatmosphere of argon gas. Rhodium(II) acetate dimer (140 mg, 0.32 mmol,0.15 eq.) was added to the solution and the resulting mixture was heatedat 75° C. for 3 h as the reaction proceeded to completion. The reactionwas concentrated to an oil and purified by silica gel columnchromatography to give 1-benzyl 3-(2-morpholinoethyl) 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(441 mg, 19% yield).

Step4:

1-Benzyl 3-(2-morpholinoethyl) 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(441 mg, 0.485 mmol) was dissolved in DMF (6.6 mL) and cooled in a wetice bath. To this solution was added oven dried cesium carbonate (316mg, 0.970 mmol, 2.0 eq.) and the resulting suspension was stirred for 30minutes. To this slurry was added1-(bromomethyl)-3-(trifluoromethoxy)benzene (157 μL, 0.970 mmol, 2.0eq.) dropwise. The reaction was allowed to warm to ambient temperatureand was held for 14 hours. The reaction was diluted with ethyl acetate(50 mL) and was washed twice with water (40 mL), brine, dried overmagnesium sulfate and concentrated. Column chromatography purificationover silica gel to give 1-benzyl 3-(2-morpholinoethyl) 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonate(480 mg, 91% yield).

Step5:

1-Benzyl 3-(2-morpholinoethyl) 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonate(480 mg, 0.440 mmol) was dissolved in DCM (6.0 mL) followed by dropwiseaddition of TFA (500 μL). The reaction was stirred for 16 hours andmonitored by LC/MS. Upon completion the reaction solution wasconcentrated to dryness. The crude was purified by the reversed-phaseHPLC gave the desired 1-benzyl 3-(2-morpholinoethyl) 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonate.

LC/MS [M+H]=783.3.

Example 98 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-(2-morpholinoethoxy)-3-oxo-2-(3-(trifluoromethoxy)benzyl)propanoicacid

Step1:

1-Benzyl 3-(2-morpholinoethyl) 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonate (248 mg, 0.32 mmol) was dissolved at room temperature in EtOAc(2.5 mL) under a blanket of Argon gas. Pd/C 10% (25 mg) was charged intothe round-bottom flask and purged three times with Argon gas. Ahydrogen-filled balloon was attached to the round bottom and purgedtwice. The reaction was monitered for completion by LC/MS. The reactionflask was purged with Argon gas upon completion. The reaction slurry wasfiltered through a bed of celite and rinsed twice with EtOAc (5.0 mL).The filtrate was concentrated and purified by reversed-phase HPLC togive the desired 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-(2-morpholinoethoxy)-3-oxo-2-(3-(trifluoromethoxy)benzyl)propanoicacid.

LC/MS [M+H]=693.2.

Example 99 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(2,3,4-trifluorobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 2,3,4-tri-fluorobenzyl bromide, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ 8.30 (bs, 1H), 7.15 (_(q), J=6.63 Hz, 1H),6.80 (q, J=8.61 Hz, 1H), 6.42 (dd, J=4.41, 12.97 Hz, 1H), 5.18 (td,J=3.88, 52.34 Hz, 1H), 4.67 (td, J=4.11, 17.65 Hz, 1H), 4.18-4.11 (m,1H), 4.10-3.93 (m, 2H), 3.55-3.41 (m, 2H); LC/MS [M+H]=550.

Example 100 Synthesis of 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Step1:

To a solution of 1,2-O-(1-Methylethylidene-α-D-xylofuranose (40 g,210.31 mmol, 1 eq.) in DMF (300 mL) was added imidazole (35.80 g, 525.78mmol, 2.5 eq.) and TBDPSCl (69.37 g, 252.37 mmol, 64.83 mL, 1.2 eq.) at0° C. under N₂ atomsphere. The mixture was stirred at 25° C. for 5 hbefore it was quenched with H₂O (1000 mL). The aqueous phase wasextracted with EtOAc (3×250 mL). The combined organic layer was washedwith brine (500 mL), dried over Na₂SO₄ and filtered. The filtrate wasconcentrated to dryness. The crude product was purified by flash silicagel chromatography to provide the product(3aR,5R,6S,6aR)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(80 g, 88.7% yield) as a colorless syrup.

Step2:

To a solution of (3aR,5R, 6S,6aR)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(80 g, 186.66 mmol, 1 eq.) in DCM (1000 mL) was added DMP (118.75 g,279.99 mmol, 86.68 mL, 1.5 eq.) at 0° C. The mixture was stirred at 25°C. for 16 h to give a white suspension. The mixture was quenched withsaturated aq. Na₂S₂O₃ (500 mL). The aqueous phase was extracted with DCM(2×500 mL). The combined organic layer was washed with brine (500 mL),dried over Na₂SO₄, filtered and concentrated to dryness. The crudeproduct was purified by silica gel column chromatography (0-17% of EtOAcin petroleum ether) to provide(3aR,5R,6aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(3aH)-one(74.1 g, 93% yield) was obtained as a colorless gum.

Step3:

To a solution of(3aR,5R,6aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(3aH)-one(40.8 g, 95.65 mmol, 1 eq) in THF (400 mL) was added MeMgBr (3 M, 47.82mL, 1.5 eq.) at 25° C. under N₂ atmosphere. The mixture was stirred at25° C. for 1 h to give a brown suspension before it was quenched withsaturated aq. NH₄Cl (500 mL). The aqueous phase was extracted with EA(3×400 mL). The organic layer was washed with brine (500 mL), dried overNa₂SO₄, filtered and concentrated to dryness. The crude product waspurified by silica gel column chromatography (0-10% of EtOAc inpetroleum ether) to provide (3aR,5R, 6R,6aR)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (41.77 g, 98.7% yield) as a colorless gum.

Step4:

To a solution of (3aR,5R, 6R,6aR)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(15 g, 33.89 mmol, 1 eq.) in DCM (150 mL) and water (15 mL, 832.63 mmol,24.57 eq.) was added TFA (150 mL, 2.03 mol, 59.78 eq.) dropwised at 0°C. The mixture was stirred at 20° C. for 1 h before it was quenched withsaturated aq. NaHCO₃ to pH7. The aqueous phase was extracted with DCM(2×230 mL). The combined organic layer was washed with brine (130 mL),dried over Na₂SO₄ and filtered. The filtrate was concentrated todryness. The crude product was purified by flash silica gel columnchromatography (0-40% of EtOAc in petroleum ether) to provide (3R, 4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methyltetrahydrofuran-2,3,4-triolas a yellow gum.

Step5:

To a solution of (3R, 4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methyltetrahydrofuran-2,3,4-triol(8.23 g, 20.44 mmol, 1 eq.) in pyridine (80 mL) was added 4-DMAP (7.49g, 61.33 mmol, 3 eq.) and Ac₂O (19.15 mL, 204.44 mmol, 10 eq.) at 20° C.The mixture was stirred at 20° C. for 16 h before it was quenched withH₂O (530 mL). The aqueous phase was extracted with EA (3×230 mL). Thecombined organic layer was washed with brine (240 mL), dried overNa₂SO₄, filtered and concentrated to dryness. The crude product waspurified by silica gel column chromatography (0-50% of EtOAc inpetroleum ether) to provide(3R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methyltetrahydrofuran-2,3,4-triyltriacetate(10.27 g, 95% yield) as a yellow gum.

Step6:

To a solution of (3R, 4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methyltetrahydrofuran-2,3,4-triyltriacetate (10.27 g, 19.43 mmol, 1 eq.) in MeCN (110 mL) was added2-chloro-9H-purin-6-amine (3.62 g, 21.37 mmol, 1.1 eq.), DBU (8.78 mL,58.28 mmol, 3 eq.) and TMSOTf (17.55 mL, 97.13 mmol, 5 eq.) at 0° C. Themixture was stirred at 0° C. for 0.5 h. Then the mixture was stirred at65° C. for 1 h before it was quenched with saturated aq. NaHCO₃ (300mL). The aqueous phase was extracted with EtOAc (2×220 mL). The combinedorganic layer was washed with brine (230 mL), dried over Na₂SO₄,filtered and concentrated to dryness. The crude product was purified byflash silica gel colunn chromatography (0-100% of EtOAc in petroleumether) to provide (2R, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diyldiacetate (5.6 g, 28% yield) as a yellow solid.

Step7:

To a solution of (2R, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diyldiacetate (5.1 g, 7.99 mmol, 1 eq.) in DMF (50 mL) was added TEA (5.56mL, 39.96 mmol, 5 eq.), 4-DMAP (292.89 mg, 2.40 mmol, 0.3 eq.) and Boc₂O(8.72 g, 39.96 mmol, 5 eq.) at 20° C. The mixture was stirred at 20° C.for 1 h to give a yellow suspension was quenched with H₂O (250 mL). Theaqueous phase was extracted with EA (3×230 mL). The combined organiclayer was washed with brine (250 mL), dried over Na₂SO₄, filtered andconcentrated to dryness. The crude product was purified by flash silicagel column chromatography (0-33% of EtOAc in petroleum ether) to provide(2R,3R,4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diyldiacetate (5.59 g, 75% yield) as a foam.

Step8:

To a solution of (2R, 3R, 4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diyldiacetate (5.59 g, 6.67 mmol, 1 eq.) in THF (60 mL) was added TBAF (1 M,in THF, 10.00 mL, 1.5 eq.) at 0° C. The reaction mixture was stirred at0° C. for 1 h before it was diluted with H₂O (150 mL). The aqueous phasewas extracted with EA (3×130 mL). The combined organic layer was washedwith brine (150 mL), dried over Na₂SO₄ and filtered. The filtrate wasconcentrated to dryness. The crude product was purified by flash silicagel chromatography (0-33% of EtOAc in petroleum ether) to provide (2R,3R, 4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diyldiacetate (3.09 g, 77% yield) as a white foam.

Step9:

To a solution of (2R, 3R, 4R,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diyldiacetate (680 mg, 1.13 mmol, 1 eq.) in toluene (5 mL) and Rh₂(OAc)₄(50.09 mg, 113.33 umol, 0.1 eq.) at 20° C. was added a solution ofdiethyl 2-diazopropanedioate (316.47 mg, 1.70 mmol, 1.5 eq.) in toluene(5 mL). The reaction mixture was heated at 95° C. for 3 hr before it wasallowed to cool to room temperature. The reaction was concentrated todryness. The crude product was purified by flash silica gelchromatography (0-25% of EtOAc in petroleum ether) to provide diethyl2-(((2R, 3R, 4R,5R)-3,4-diacetoxy-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-3-methyltetrahydrofuran-2-yl)methoxy)malonate(585 mg, 59% yield) as a white foam.

Step10:

To a solution of diethyl 2-(((2R, 3R, 4R,5R)-3,4-diacetoxy-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-3-methyltetrahydrofuran-2-yl)methoxy)malonate(535 mg, 705.65 umol, 1 eq.) in DMF (5 mL) was added K₂CO₃ (195.06 mg,1.41 mmol, 2 eq.) and stirred at 20° C. for 30 min beforebromomethylbenzene (167.62 uL, 1.41 mmol, 2 eq.) was added to themixture and stirred at 20° C. for 15.5 h. The reaction was quenched withH₂O (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL). Thecombined organic layer was washed with brine (10 mL), dried over Na₂SO₄filtered and concentrated to dryness. The crude product was purified byflash silica gel chromatography (0-25% of EtOAc in petroleum ether) toprovide diethyl 2-benzyl-2-(((2R, 3R, 4R,5R)-3,4-diacetoxy-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-3-methyltetrahydrofuran-2-yl)methoxy)malonateas colorless gum.

Step11:

To a solution of diethyl 2-benzyl-2-(((2R, 3R, 4R,5R)-3,4-diacetoxy-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino-2-chloro-9H-purin-9-yl)-3-methyltetrahydrofuran-2-yl)methoxy)malonate(1.05 g, 1.24 mmol, 1 eq.) in DCM (10 mL) was added TFA (1.5 mL) at 0°C. The mixture was stirred at 25° C. for 16 h before it was quenchedwith saturated aq. NaHCO₃ until it reached pH7. The aqueous phase wasextracted with DCM (2×50 mL). The combined organic layer was washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to drynessto provide diethyl 2-benzyl-2-(((2R, 3R, 4R,5R)-3,4-diacetoxy-5-(6-amino-2-chloro-9H-purin-9-yl)-3-methyltetrahydrofuran-2-yl)methoxy)malonateas a foam which was used in the next step directly without furtherpurification.

Step12:

The mixture of diethyl 2-benzyl-2-(((2R, 3R, 4R,5R)-3,4-diacetoxy-5-(6-amino-2-chloro-9H-purin-9-yl)-3-methyltetrahydrofuran-2-yl)methoxy)malonate(736 mg, 1.14 mmol, 1 eq.) in saturated NH₃ in MeOH (10 mL) was stirredat 10° C. for 16 h before the mixture was concentrated to dryness. Thecrude product was purified by flash silica gel column chromatography(0-100% of EtOAc in petroleum ether) to provide diethyl 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(448 mg, 67% yield) as a white solid.

Step13:

To a solution of diethyl 2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(150 mg, 265.96 umol, 1 eq.) in EtOH (2 mL) was added LiOH.H₂O (55.80mg, 1.33 mmol, 5 eq.) in H₂O (0.5 mL) at 10° C. The mixture was stirredat 50° C. for 4 h before it was concentrated to dryness. The residue wasdissolved in H₂O (50 ml). The aqueous phase was extracted with EA (2×50mL). The aqueous phase was adjusted to pH 2-3 with 1 N aq. HCl. Theaqueous phase was extracted with EtOAc (3×50 mL). The combined organiclayer was washed with brine (50 mL), dried over Na₂SO₄ and filtered. Thefiltrated was concentrated to dryness and then lyophilization to provide2-(((2R, 3S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.77 (br s, 2H), 7.19 (br d,J=6.53 Hz, 2H), 7.03-7.14 (m, 3H), 5.80 (d, J=8.03 Hz, 1H), 4.42 (d,J=8.03 Hz, 1H), 4.00 (m, 1H), 3.60-3.73 (m, 2H), 3.22-3.40 (m, 2H), 1.11(s, 3H); LC/MS [M+H]=508.0.

Example 101 Synthesis of 2-(((2S, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Step1:

To a mixture of (2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-fluorotetrahydrofuran-3-ol(2.6 g, 4.80 mmol, 1 eq) in MeCN (20 mL) was added TCDI (1.28 g, 7.19mmol, 1.5 eq) at 0° C. , the mixture was stirred at 25° C. for 17 hours.Additional of TCDI (1.28 g, 7.19 mmol, 1.5 eq) was added into the abovemixture and the mixture was stirred at 25° C. for 5 hours. The mixturewas partitioned between EtOAc (100 mL) and water (80 mL), the aqueousphase was extracted with EtOAc (3×40 mL), the combined extracts werewashed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a crude product, which waspurified by flash silica gel column chromatography (17-33% of EtOAc inpetroleum ether) to give O-((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-fluorotetrahydrofuran-3-yl)1H-imidazole-l-carbothioate (2.3 g, 59% yield) as a light yellow gum.

Step2;

To a mixture of O-((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-fluorotetrahydrofuran-3-yl)1H-imidazole-l-carbothioate (300 mg, 459.97 umol, 1 eq) in toluene (5mL) was added AIBN (15.11 mg, 91.99 umol, 0.2 eq) under N₂ atmosphere,the mixture was heated to 110° C. and (n-Bu)₃SnH (182.56 uL, 689.96umol, 1.5 eq) was added into the above mixture dropwise under under N₂atmosphere. The mixture was stirred at 110° C. for before the mixturewas quenched with saturated KF (20 mL), partitioned between EtOAc (100mL) and water (10 mL), the organic phase was washed with brine (2×50mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a crude product, which was purified by flashsilica gel chromatography (0-40% of EtOAc in petroleum ether) to give9-((2R,3S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrofuran-2-yl)-2-chloro-9H-purin-6-amine as awhite powder.

Step3:

To a mixture of 9-((2R,3S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrofuran-2-yl)-2-chloro-9H-purin-6-amine (1.20 g,2.28 mmol, 1 eq) in DMF (10 mL) was added Boc₂O (1.10 g, 5.02 mmol, 2.2eq), DMAP (83.60 mg, 684.31 umol, 0.3 eq) and TEA (793.73 uL, 5.70 mmol,2.5 eq). The mixture was stirred at 25° C. under N₂ atmosphere for 0.5hours before the mixture was partitioned between EtOAc (100 mL) andwater (50 mL), the aqueous phase was extracted with EtOAc (30 mL×4), andthe combined extracts were washed with water (100 mL×2), brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give the crude bis-N-Boc protected product (1.8 g) as yellowgum which was used for next step directly without purification.

Step4:

To a mixture of the crude bis-N-Boc protected product (1.68 g, 2.31mmol, 1 eq) in THF (15 mL) was added TBAF (1 M, 3.47 mL, 1.5 eq) at 0°C., the mixture was stirred at 0° C. for 0.5 hour before the reactionmixture was quenched with cooled water (50 mL), then extracted withEtOAc (3×80 mL), the combined extracts were washed with cooled water(2×80 mL), brine (80 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a crude product as lightyellow oil, which was purified by flash silica gel chromatography (0-60%of EtOAc in petroleum ether) to give the desired alcohol as a yellowoil.

Step5:

To a mixture of the alcohl product from the previous step (850 mg, 1.74mmol, 1 eq) in toluene (10 mL) was added Rh2(OAc)4 (77.00 mg, 174.21umol, 0.1 eq) and diethyl 2-diazomalonate (421.62 mg, 2.26 mmol, 1.3eq). The mixture was stirred at 115° C. under N₂ atmosphere for 1 hourbefore the mixture was cooled to room temperature and partitionedbetween EtOAc (100 mL) and water (20 mL), the organic phase was washedwith water (20 mL), brine (20 mL), dried over anhydrous Na2SO₄, filteredand concentrated under reduced pressure to give a crude product, whichwas purified by flash silica gel chromatography (0-60% of EtOAc inpetroleum ether) to give diethyl2-(((2S,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate8 (480 mg, 41% yield) as a light yellow oil.

Steps 6-8:

Proceeding as described in Example 2 above, the title compound wasprepared and isolated as a white solid.

LC/MS [M+H]=480.3.

Example 102 Synthesis of 2-(((2S, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3-azido-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Proceeding as described in Example 18 above, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz): δ 8.20 (s, 1H), 7.03-7.20 (m, 2H), 7.05 (dd,J=5.1, 1.6 Hz, 3H), 5.82 (d, J=4.5 Hz, 1H), 4.76-4.78 (m, 1H), 4.48 (brd, J=6.3 Hz, 1H), 4.25 (t, J=5.9 Hz, 1H), 3.88 (d, J=4.3 Hz, 2H), 3.29(d, J=5.5 Hz, 2H); LC/MS [M+H]=519.4.

Example 103 Synthesis of 2-4(2S, 3R, 4R,5R)-3-amino-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Step1:

To a colorless solution of diethyl 2-(((2S, 3R, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3-azido-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(100 mg, 173.92 umol, 1 eq) in pyridine (2 mL) was added PPh₃ (72.99 mg,278.27 umol, 1.6 eq). The colorless solution was stirred at 25° C. for 1hr. To the colorless solution was added NH₄OH (0.40 mL, 2.91 mmol, 16.72eq). The colorless solution was stirred at 25° C. for 16 h before it wasconcentrated to give crude diethyl2-(((2S,3R,4R,5R)-3-amino-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(190 mg) as a colorless gum which was used in next step directly.

Step2:

To a colorless solution of crude diethyl 2-(((2S, 3R, 4R,5R)-3-amino-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(190 mg, 173.05 umol, 1 eq) in THF (3 mL) was added LiOH (1 M, 1.73 mL,10 eq). The colorless solution was stirred at 25° C. for 16 h before itwas diuted with water (2 mL), and extracted with ethyl acetate (3×2 mL).To the water layer was added 1N aq. HCl to adjust the pH to 6. The waterlayer was extracted with ethyl acetate (3×2 mL). The water layer wasdried by lyophilization to give white solid (190 mg). This crude wassuspended in 10 mL of THF and filtered. The filtration was concentratedto give crude product which was purified by reversed-phase HPLC toprovide 2-(((2S, 3R, 4R, 5R)-3-amino-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid as a white solid.

¹H NMR (CD₃OD, 400 MHz): δ 8.32 (br s, 1H), 7.15 (br s, 5H), 5.93 (br s,1H), 4.50-4.60 (m, 2H), 4.02-4.10 (m, 1H), 3.89 (br s, 1H), 3.78 (br d,J=10.0 Hz, 1H), 3.18-3.27 (m, 2H); LC/MS [M+H]=493.4.

Example 104 Synthesis of 2-(((2R, 3S, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-azido-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Proceeding as described in Example 18 above, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz): δ 8.43 (s, 1H), 7.20-7.30 (m, 2H), 7.05-7.11(m, 3H), 6.39 (d, J=6.53 Hz, 1H), 4.60 (t, J=7.53 Hz, 1H), 4.45-4.50 (m,1H), 4.06-4.14 (m, 2H), 3.89-4.01 (m, 1H), 3.33-3.49 (m, 2H); LC/MS[M+H]=518.9.

Example 105 Synthesis of 2-(((2R, 3S, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Step1:

To a solution of(2R,3R,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2-4(4methoxyphenyl)diphenylmethoxy)methyl)tetrahydrofuran-3-ol (10 g, 14.53 mmol, 1 eq.) in DCM (100 mL) was added4-DMAP (5.32 g, 43.59 mmol, 3 eq.) and Tf₂O (2.88 mL, 17.43 mmol, 1.2eq.) at 0° C. The mixture was stirred at 0° C. for 1 hr before it wasquenched with H₂O (500 mL). The aqueous phase was extracted with DCM(2×340 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated to dryness. The crude product was purified by flashsilica gel chromatography (0-60% of EtOAc in petroleum ether) to providethe triflate product (9.62 g, 80.7% yield) was obtained as a white foam.

Step2:

To a solution of the triflate product from the previous step (6.6 g,8.05 mmol, 1 eq.) in DMF (70 mL) was added AcONa (6.60 g, 80.45 mmol, 10eq.) at 25° C. The mixture was stirred at 25° C. for 16 hr before themixture was diluted with H₂O (250 mL). The aqueous phase was extractedwith EA (2×200 mL). The combined organic layer was washed with brine(250 mL), dried over Na₂SO₄ and filtered. The filtrate was concentratedto dryness.

The crude product was purified by flash silica gel chromatography (0-50%of EtOAc in petroleum ether) to provide the acetate product (4.35 g, 74%yield) was as a foam.

Step3:

To a mixture of the acetate product from the prevous step (4.35 g, 5.96mmol, 1 eq.) in DMF (40 mL) was added TEA (3.01 g, 29.78 mmol, 4.15 mL,5 eq.), 4-DMAP (218.30 mg, 1.79 mmol, 0.3 eq.) and tert-butoxycarbonyltert-butyl carbonate (6.50 g, 29.78 mmol, 5 eq.) at 0° C. The mixturewas stirred at 25° C. for 1 hr it was diluted H₂O (250 mL). The aqueousphase was extracted with EtOAc (3×240 mL). The combined organic layerwas washed with brine (250 mL), dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to dryness. The crude product was purified byflash silica gel chromatography (0-20% of EtOAc in petroleum ether) toprovide the bis-N-Boc product (4.4 g, 64% yield) as a foam.

Step4:

To a solution of the bis-N-Boc product from the previous step (4.4 g,4.73 mmol, 1 eq.) in MeOH (150 mL) was added TEA (150 mL) and H₂O (50mL) at 20° C. The mixture was stirred at 20° C. for 1 hr before H₂O (120mL) was added to the reaction mixture. The aqueous phase was extractedwith EtOAc (3×120 mL). The combined organic layer was washed with brine(130 mL), dried over Na₂SO₄ and filtered. The filtrate was concentratedto dryness. The crude product was purified by flash silica gelchromatography (0-20% of EtOAc in petroleum ether) to provide thealcohol product (3.59 g, 84% yield) as a white foam.

Step5:

To a solution of DAST (1.73 g, 10.74 mmol, 1.42 mL, 6 eq.) in DCM (20mL) was added pyridine (1.5 mL, 18.58 mmol, 10.39 eq.) and the alcoholproduct from the previous step (1.59 g, 1.79 mmol, 1 eq.) in DCM (20 mL)at 0° C. The mixture was stirred at 20° C. for 3 hr before the mixturewas diluted with H₂O (130 mL). The aqueous phase was extracted with DCM(3×120 mL). The combined organic layer was washed with brine (130 mL),dried over Na₂SO₄ and filtered. The filtrate was concentrated todryness. The crude product was purified by flash silica gelchromatography (0-20% of EtOAc in petroleum ether) to provide thefluoride product (344 mg, 22% yield) was obtained as a yellow foam.

Step6:

To a solution of the fluoride product from the previous step (344 mg,386.30 umol, 1 eq.) in DCM (3 mL) was added TFA (150 uL) in DCM (3 mL)at 0° C. The mixture was stirred at 0° C. for 5min before TEA was addedto the reaction mixture to adjust the pH to 7. Then the mixture wasconcentrated to dryness. The crude product was purified by flash silicagel chromatography (0-25% of EtOAc in petroleum ether) to provide theprimary alcohol product (226 mg, 68% yield) as a yellow solid.

Steps 7-11:

Proceeding as described in Example 1 above, the title compound wasprepared and isolated as a white solid.

¹H NMR (DMSO-d6, 400 MHz): δ 8.46 (br s, 1H), 7.84 (br s, 2H), 7.13-7.25(m, 5H), 5.94 (br d, J=6.63 Hz, 1H), 5.85 (d, J=8.00 Hz, 1H), 4.94-5.17(m, 1H), 4.77-4.91 (m, 1H), 4.37-4.48 (m, 1H), 3.66 (br s, 2H), 3.21 (brs, 2H); LC/MS [M+H]=495.9.

Example 106 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Step1:

To a solution of(6aR,8R,9R,9aR)-8-(6-amino-2-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yltrifluoromethanesulfonate (5 g, 7.39 mmol, 1 eq) in DMF (60 mL) wasadded LiCl (1.57 g, 36.97 mmol, 5 eq). The colorless solution wasstirred at 25° C. for 16 h before it was poured into 100 mL of water,and extracted with ethyl acetate (100 mL) twice. The organic was washedwith water (200 mL), brine (200 mL), dried by Na₂SO₄ and concentrated.The crude was purified by Combi-flash (20 g silica gel, ethyl acetate inpetrol ether from 20-60%) to give2-chloro-9-((6aR,8R,9S,9aR)-9-chloro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-9H-purin-6-amine(2.85 g, 69% yield) as a white solid.

Step2:

To a colorless solution of2-chloro-9-((6aR,8R,9S,9aR)-9-chloro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-9H-purin-6-amine(2.80 g, 4.98 mmol, 1 eq) in DMF (35 mL) was added 4-DMAP (121.60 mg,995.31 umol, 0.2 eq), TEA (3.02 g, 29.86 mmol, 4.16 mL, 6 eq) and(Boc)₂O (5.43 g, 24.88 mmol, 5.72 mL, 5 eq). The yellow solution wasstirred at 25° C. for 1 hr. The reaction was diluted with water (60 mL)and extracted with ethyl acetate (60 mL) twice. The combined organicswere washed with water (100 mL), brine (100 mL), dried by Na₂SO₄, andfiltered. The filtrate was concentrated to give crude (4.2 g) as ayellow gum. The crude was purified by Combi-flash (20 g silica gel whichwas treated with TEA, ethyl acetate in petrol ether from 10-25%) to givethe bis-N-Boc product (3.35 g, 85.95% yield) as a white solid.

Step3:

To a colorless solution of the bis-N-Boc product from the previous step(3.35 g, 4.39 mmol, 1 eq) in THF (35 mL) was added TBAF (1 M, 17.57 mL,4 eq) at 0° C. The solution was stirred at 0° C. for 1 hr. The reactionwas diluted with ice-water (50 mL) and extracted with ethyl acetate (50mL) twice. The organic was washed with water (100 mL), brine (100 mL),dried by Na₂SO₄, and filtered. The filtration was concentrated to givecrude. The crude was purified by Combi-flash (12 g silica gel which wastreated with TEA, ethyl acetate in petrol ether from 30-80%) to give the3,5-diol product (1.95 g, 81% yield) as a white solid.

Step4:

To a colorless solution of the 3,5-diol product from the previous step(1.94 g, 3.73 mmol, 1 eq) in toluene (40 mL) was added Rh₂(OAc)₄ (247.17mg, 559.23 umol, 0.15 eq). The green suspension was heated to 50° C.under N₂. To the suspension was added diethyl 2-diazomalonate (902.27mg, 4.85 mmol, 1.3 eq). The green suspension was stirred at 50° C. for36 h. The reaction was diluted with water (20 mL), and extracted withethyl acetate (20 mL) twice. The organic was washed with brine (40 mL),dried by Na₂SO₄, and filtered. The filtrate was concentrated to givecrude (3.2 g) as a purple gum. The crude was purified by Combi-flash (20g silica gel which was treated with TEA, ethyl acetate in petrol etherfrom 20-70%) to give diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate(1060 mg, 40% yield) as a yellow gum.

Step5:

To a yellow solution of diethyl 2-(((2R, 3R,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate(1.25 g, 1.84 mmol, 1 eq) in DMF (15 mL) was added K₂CO₃ (509.22 mg,3.68 mmol, 2 eq). The yellow suspension was stirred at 25° C. for 0.5hr. To the yellow suspension was added bromomethylbenzene (378.11 mg,2.21 mmol, 262.57 uL, 1.2 eq). The yellow suspension was stirred at 25°C. for 16 hr. Additional amount of K₂CO₃ (500 mg) was added and theyellow suspension was stirred at 25° C. for additional 6 hr. The yellowsuspension was diluted with water (20 mL) and extracted with ethylacetate (20 mL) twice. The organic was washed with water (40 mL), brine(40 mL), dried by Na₂SO₄, and filtered. The filtrate was concentrated togive crude (2.6 g) as a yellow gum. The crude was purified byCombi-flash (20 g silica gel, ethyl acetate in petrol ether from 15-40%)to give diethyl 2-benzyl-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate(855 mg, 59% yield) as a white solid.

Step6:

To a colorless solution of diethyl 2-benzyl-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonate(400 mg, 520.40 umol, 1 eq) in DCM (6.7 mL) was added TFA (1.54 g, 13.51mmol, 1 mL, 25.95 eq) at 0° C. The yellow solution was stirred at 25° C.for 5 hr. The reaction was diluted with saturated aq. NaHCO₃ (20 mL) andextracted with ethyl acetate (20 mL) for three times. The organic waswashed with brine (50 mL), dried by Na₂SO₄, and filtered. The filtratewas concentrated to give crude (330 mg) as a yellow gum. The crude waspurified by Combi-flash (4 g silica gel, ethyl acetate in petrol etherfrom 30-80%) to give 290 mg of colorless gum. The gum was dried bylyophilization to provide diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(260 mg, 81.6% yield) as a white solid.

Step7:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonate(110 mg, 193.52 umol, 1 eq) in EtOH (4 mL), was added LiOH (1 M, 1.94mL, 10 eq). The reaction mixture was stirred at 25° C. for 8 h. To thesolution was added 2N HCl(aq.) to adjust the pH to 5, and the mixturewas extracted with EtOAc(4×5 mL). The combined organics were dried overhydrous Na₂SO₄, and filtered. The filtration was concentrated. The crudewas purified by preparative reversed-phase HPLC, and dried bylyophilization to give 2-4(2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid (22.0 mg, 22% yield) as a white powder.

¹H NMR (DMSO-d6, 400 MHz): δ 0.41 (s, 1H), 7.85 (br s, 2H), 7.16-7.22(m, 2H), 7.10-7.15 (m, 3H), 6.41 (d, J=6.3 Hz, 1H), 6.16 (br s, 1H),4.75-4.83 (m, 1H), 4.54 (br t, J=7.5 Hz, 1H), 3.97 (m, 1H), 3.91 (m,2H), 3.24 (s, 2H); LC/MS [M+H]=512.4.

Example 107 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonic acid

Step1:

To a solution of compound (2R, 3S, 4R,5R)-5-((benzoyloxy)methyl)-3-fluorotetrahydrofuran-2,4-diyl dibenzoate(4 g, 8.61 mmol, 1 eq) in DCM (12 mL) was added HBr (6.56 g, 28.36 mmol,4.4 mL, 35% purity in AcOH, 3.29 eq). The solution was stirred at 25° C.for 16 hr. The pH of the reaction mixture was adjusted to 8 withsaturated NaHCO₃ (aq.), then extracted with EtOAc (50 mL×3). Thecombined organics were washed with brine (50 mL×2). The solution wasdried with Na₂SO₄ and filtered. The filtration was concentrated to givethe bromide product (3.59 g, crude) as a yellow oil.

Step2:

To a solution of compound((2R,3R,4S,5R)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydrofuran-2-yl)methylbenzoate (1.91 g, 10.18 mmol, 1.2 eq.) in anhydrous MeCN (100 mL) at 0°C. was added NaH (407.12 mg, 10.18 mmol, 60% purity, 1.2 eq.). Thereaction mixture was stirred further for 20 min. A solution of compound2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3.59 g, 8.48 mmol, 1 eq.) inMeCN (20 mL) was added dropwise over 10 min. The mixture was stirred at25° C. for 1.5 h before it was quenched with water (30 mL) and extractedwith EtOAc (50 mL×3). The combined organic layers were washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to givea residue as yellow foam. The crude was purified by columnchromatography on a 40 g silica gel column (eluted with 10-70% of EtOAcin petroleum ether) to provide((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluorotetrahydrofuran-2-yl)methylbenzoate (3.8 g, 84% yield) as a white foam.

Step3:

To a solution of NH₃ in THF (40 mL) was added the di-chloro product fromthe previous step (2 g, 3.77 mmol, 1 eq). The reaction mixture wasstirred at 25° C. for 16 hours in autoclave. The reaction mixture wasconcentrated to give a mixture of(2R,3R,4S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((benzoyloxy)methyl)-4-fluorotetrahydrofuran-3-ylbenzoate and(2R,3R,4S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((benzoyloxy)methyl)-4-fluorotetrahydrofuran-3-ylbenzoate (2.2 g) as a white solid. This crude mixture was used in thenext step directly without further purification.

Step4:

To a solution of a mixture of(2R,3R,4S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((benzoyloxy)methyl)-4-fluorotetrahydrofuran-3-ylbenzoate and(2R,3R,4S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((benzoyloxy)methyl)-4-fluorotetrahydrofuran-3-ylbenzoate (6.60 g, 16.22 mmol, 1 eq.) in MeOH (100 mL), was addedCH₃ONa/MeOH (1.5 M, 108.16 mL, 10 eq.) under N₂ atmosphere. The reactionmixture was stirred at 25° C. for 1 hr. The pH of the reaction mixturewas adjusted to 5-6 with 2N HCl (aq.), extracted with EtOAc (150 mL×4).The organic phase was collected and washed with brine (30 mL×3), driedwith anhydrous Na₂SO₄, filtered and concentrated to give a residue (5.5g) as a yellow oil. The crude was purified by combi-flash on a 40 gsilica gel (eluted with 25-70% of EtOAc in petroleum ether) to give(2R,3R,4S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol(2.45 g, yield :46%) as a white solid.

Steps 5-11:

Proceeding as described in Example 1 above, the title compound wasprepared and isolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 13.49 (br s, 2H), 7.58 (br s, 2H),7.24-7.30 (m, 1H), 7.13-7.24 (m, 5H), 6.59 (d, J=3.76 Hz, 1H), 6.43 (dd,J=16.69, 4.14 Hz, 1H), 5.95 (br s, 1H), 5.00-5.19 (m, 1H), 4.42 (br d,J=18.07 Hz, 1H), 3.95 (m, 1H), 3.78 (br s, 2H), 3.21 (br s, 2H); LC/MS[M+H]=494.9.

Example 108 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonic acid

Proceeding as described in Example 2 above but substituting diethyl2-(((2R,3R,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonatewith diethyl2-(((2R,3R,4S,5R)-5-(4-N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate,the title compound was prepared and isolated as a white solid.

¹H NMR (DMSO-d6, 400 MHz): δ 12.30-14.28 (br s, 2H), 7.77 (d, J=8.4 Hz,2H), 7.57 (br s, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.21-7.30 (m, 1H), 6.59(d, J=4.0 Hz, 1H), 6.44 (dd, J=16.4, 4.0 Hz, 1H), 5.97 (br s, 1H),5.00-5.23 (m, 1H), 4.42 (m, 1H), 3.92-4.01 (m, 1H), 3.84 (br d, J=4.4Hz, 2H), 3.24 (s, 2H); LC/MS [M+H]=538.9.

Example 109 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(4-amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-benzylmalonic acid

Step1:

To a mixture 3,5-di-O-benzoyl-2-deoxy -2-f1uoro-α-D-arabinofuranosylbromide (5 g, 10.77 mmol, 1 eq) and4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (2.24 g, 11.84 mmol, 1.1 eq)in anhydrous MeCN (80 mL) was added DBU (4.92 g, 32.30 mmol, 4.87 mL, 3eq) at 0° C. The mixture was stirred at 0° C. for 5 minutes and thenTMSOTf (10.77 g, 48.45 mmol, 8.75 mL, 4.5 eq) was added dropwise. Themixture was stirred at 0° C. for 30 mins, and then stirred at 70° C. for17 hours before the mixture was cooled to room temperture and dilutedwith EtAOc (200 mL), and the organic layer was washed with saturatedNaHCO₃ (100 mL), brine (100 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a crude product, which was purified by flash silica gelchromatography (0-17% of ethyl acetate in petroleum ether) to give ((2R,3R, 4S,5R)-3-(benzoyloxy)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-fluorotetrahydrofuran-2-yl)methylbenzoate (3 g, 51.7% yield) as a colorless oil.

Step2:

To the product from the previous step (2.5 g, 4.71 mmol, 1 eq) was addedsaturated NH₃ in MeOH (188.21 umol, 30 mL). The mixture was stirred at25° C. for 17 hours before the mixture was concentrated under reducedpressure to give a crude product, which was purified by flash silica gelchromatography (0-80% of ethyl acetate in petroleum ether) to give (2R,3R, 4S,5R)-5-(4-amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-olas a white powder.

Step3:

To a mixture of the diol product from the previous step (720 mg, 2.37mmol, 1 eq) in DMF (10 mL) was added TBDPSCl (582.16 uL, 2.27 mmol) andimidazole (403.53 mg, 5.93 mmol, 2.5 eq). The mixture was stirred at 25°C. for 17 hours before the mixture was partitioned between water (50 mL)and EA (80 mL), the aqueous phase was extracted with EA (3×30 mL), thecombined extracts were washed with water (2×80 mL), brine (80 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give a crude product, which was purified by flash silica gelchromatography (0-75% of ethyl acetate in petroleum ether) to give(2R,3R,4S,5R)-5-(4-amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-fluorotetrahydrofuran-3-ol as white powder.

Step4:

To a mixture of the product from the previous step (1.32 g, 2.44 mmol, 1eq) in DMF (10 mL) was added TEA (1.23 g, 12.18 mmol, 1.69 mL, 5 eq) ,4-DMAP (89.25 mg, 730.53 umol, 0.3 eq) and tert-butoxycarbonyltert-butyl carbonate (2.66 g, 12.18 mmol, 2.80 mL, 5 eq). The mixturewas stirred at 20° C. for 2 hours before the mixture was partitionedbetween EA (50 mL) and water (50 mL), the aqueous phase was extractedwith EA (15 mL×3), and the combined extracts were washed with water (50mL×2), brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography (0-14% of ethyl acetate inpetroleum ether) to give tri-Boc protected product (1 g, 47% yield) as acolorless oil.

Step5:

To a mixture of the tri-Boc protected product from the previous step(900 mg, 1.07 mmol, 1 eq) in MeOH (10 mL) was added NH₄F (158.27 mg,4.27 mmol, 4 eq) at 25° C. The mixture was stirred at 25° C. for 15 hourbedore the mixture was quenched with cool water (40 mL), extracted withEA (50 mL×3), the combined extracts were washed with water (50 mL×2),brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byflash silica gel chromatography (0-25% of ethyl acetate in petroleumether) to give the primary alcohol product (470 mg, 70% yield) as afoam.

Step6:

To a mixture of the primary alcohol product from the previous step (360mg, 596.00 umol, 1 eq) in toluene (5 mL) was added Rh₂(OAc)₄ (26.34 mg,59.60 umol, 0.1 eq) , the mixture was stirred at 95° C. , and thendiethyl 2-diazomalonate (166.43 mg, 894.00 umol, 1.5 eq) in toluene (2mL) was added dropwise into the above mixture. The mixture was stirredat 95° C. under N₂ atmosphere for 3 hours to give a green mixture. Themixture was cooled to room temperature and concentrated under reducedpressure to give a crude product, which was purified by flash silica gelchromatography (0-20% of ethyl acetate in petroleum ether) to givediethyl 2-(((2R, 3R, 4S,5R)-5-(4-((N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(330 mg, 68% yield) as colorless oil.

Steps 7-9:

Proceeding as described in Example 2 above but substituting diethyl2-(((2R,3R,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonatewith diethyl 2-(((2R, 3R, 4S,5R)-5-(4-((N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate,the title compound was prepared and isolated as a white solid.

LC/MS [M+H]=496.1.

Example 110 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-nitrobenzyl)malonicacid

Proceeding as described in Example 2 above but substituting benzylbromide with 4-nitrobenzyl bromide, the title compound was prepared andisolated as a white solid.

¹H NMR (CD₃OD, 400 MHz) δ 8.23 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.50 (d,J=8.4 Hz, 2H), 6.43 (dd, J=12.0, 4.80 Hz, 1H), 5.08-5.26 (m, 1H),4.62-4.74 (m, 1H), 4.13-4.19 (m, 1H), 3.95-4.11 (m, 2H), 3.45-3.57 (m,2H); LC/MS [M+H]=541.3.

Example 111 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-aminobenzyl)malonicacid

Step1:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(4-nitrobenzyl)malonate(8.16 g, 9.09 mmol, 1 eq.) in EtOH (100 mL) was added PtO₂ (310.86 mg,1.37 mmol, 1.51e-1 eq.) under H₂ (15 psi). The mixture was stirred at25° C. for 4 h before the mixture was filtered through a pad of celite.The filtrate was concentrated to dryness to provide diethyl2-(4-aminobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(7.5 g) as an off-white foam.

Step2:

To a solution of the amino product from the previous step (1 g, 1.15mmol, 1 eq.) in DCM (10 mL) was added TFA (1.5 mL, 20.26 mmol, 17.57eq.) at 0° C. The mixture was stirred at 25° C. for 3 h before thereaction mixture was washed with saturated aq. NaHCO₃ to adjust the pHto 7. The aqueous phase was extracted with EtOAc (3×50 mL). The combinedorganic layer was washed with brine (50 mL), dried over Na₂SO₄ andfiltered. The filtrate was concentrated to dryness. The crude productwas purified by flash silica gel chromatography (0-100% of ethyl acetatein petroleum ether) to provide diethyl2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-aminobenzyl)malonate(512 mg, 78% yield) as a yellow gum.

Step3:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-aminobenzyl)malonate(512 mg, 903.05 umol, 1 eq.) in EtOH (5 mL) was added LiOH (108.14 mg,4.52 mmol, 5 eq.) in H₂O (1 mL) at 25° C. The mixture was stirred at 50°C. for 16 h before the mixture was concentrated to dryness. The residuewas dissolved in H₂O (50 mL). The aqueous phase was extracted with EtOAc(2×50 mL). The aqueous phase was adjusted to pH to 2-3 with 1 N aq. HCl.The aqueous phase was lyophilizated. The crude product was purified bypreparative reversed-phase HPLC to provide 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-aminobenzyl)malonicacid (76.4 mg, 16% yield) as an off-white solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.29 (d, J=1.76 Hz, 1H), 7.88 (br s, 2H),6.92 (d, J=8.53 Hz, 2H), 6.50 (br d, J=7.78 Hz, 2H), 6.34 (dd, J=13.93,4.64 Hz, 1H), 6.01 (br s, 1H), 5.14-5.31 (m, 1H), 4.51 (br d, J=17.57Hz, 1H), 3.97-4.02 (m, 1H), 3.80 (m, 2H), 3.07 (s, 2H); LC/MS [M+H]=511.

Example 112 Synthesis of 2-(4-acetamidobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid

Step1:

To a solution of diethyl 2-(4-aminobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(1.49 g, 1.72 mmol, 1 eq.) in AcOH (15 mL) was added Ac₂O (262.72 mg,2.57 mmol, 241.03 uL, 1.5 eq.) at 25° C. The mixture was stirred at 70°C. for 2 h before the reaction was quenched with H₂O (100 mL). Theaqueous phase was extracted with EA (3×50 mL). The combined organiclayer was washed with brine (150 mL), dried over Na₂SO₄ and filtered.The filtrate was concentrated to provide diethyl2-(4-acetamidobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(2.35 g) as a yellow oil.

Steps 2-3:

Proceeding as described in Example 2 above from diethyl2-(4-acetamidobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonateto 2-(4-acetamidobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)malonicacid, the title compound was prepared and isolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 9.83 (s, 1H), 8.27 (d, J=1.76 Hz, 1H), 7.88(br s, 2H), 7.37 (d, J=8.28 Hz, 2H), 7.12 (d, J=8.53 Hz, 2H), 6.35 (dd,J=13.43, 4.64 Hz, 1H), 5.15-5.35 (m, 1H), 4.51 (m, 1H), 4.01 (q, J=4.85Hz, 1H), 3.88 (br d, J=4.52 Hz, 2H), 3.20 (s, 2H),1.99 (s, 3H); LC/MS[M+H]=553.1.

Example 113 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-benzamidobenzyl)malonicacid

Step1:

To a solution of diethyl 2-(4-aminobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(1 g, 1.15 mmol, 1 eq.) in DCM (20 mL) was added TEA (240.72 uL, 1.73mmol, 1.5 eq.) and BzCl (200.92 uL, 1.73 mmol, 1.5 eq.) at 0° C. Themixture was stirred at 25° C. for 2 h before the reaction was dilutedwith H₂O (130 mL). The aqueous phase was extracted with EtOAc (3×130mL). The combined organic layer was washed with brine (150 mL), driedover Na₂SO₄ and filtered. The filtrate was concentrated to dryness. Thecrude product was purified by flash silica gel chromatography (0-25% ofethyl acetate in petroleum ether) to provide diethyl2-(4-benzamidobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(780 mg, 65% yield) as a yellow foam.

Steps 2-3:

Proceeding as described in Example 2 above from diethyl2-(4-benzamidobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonateto 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-benzamidobenzyl)malonicacid, the title compound was prepared and isolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 10.16 (s, 1H), 8.29 (d, J=2.01 Hz, 1H),7.90-7.94 (m, 2H), 7.87 (br s, 2H), 7.49-7.61 (m, 5H), 7.20 (d, J=8.78Hz, 2H), 6.36 (dd, J=13.55, 4.52 Hz, 1H), 5.16-5.36 (m, 1H), 4.53 (m,1H), 3.98-4.06 (m, 1H), 3.91 (br d, J=4.77 Hz, 2H), 3.24 (s, 2H); LC/MS[M+H]=615.1.

Example 114 Synthesis of2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methylsulfonamido)benzyl)malonicacid

Step1:

To a solution of diethyl 2-(4-aminobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(1.5 g, 1.73 mmol, 1 eq.) in DCM (20 mL) was added TEA (262.51 mg, 2.59mmol, 361.09 uL, 1.5 eq.), DMAP (21.13 mg, 172.95 umol, 0.1 eq.) andMsCl (401.58 uL, 5.19 mmol, 3 eq.) at 0° C. The mixture was stirred at25° C. for 2 hr before the mixture was quenched with H₂O (50 mL). Theaqueous phase was extracted with DCM (3×50 mL). The combined organiclayer was washed with brine (50 mL), dried over Mg₂SO₄ and filtered. Thefiltrate was concentrated to dryness. The crude product was purified byflash silica gel chromatography (0-40% of ethyl acetate in petroleumether) to provide diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(4-(methylsulfonamido)benzyl)malonate(900 mg, 55% yield) as a white foam.

Steps 2-3:

Proceeding as described in Example 2 above from diethyl 2-4(2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(4-(methylsulfonamido)benzyl)malonateto2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methylsulfonamido)benzyl)malonicacid, the title compound was prepared and isolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 9.60 (s, 1H), 8.26 (d, J=1.51 Hz, 1H), 7.87(br s, 2H), 7.18 (d, J=8.53 Hz, 2H), 7.00 (d, J=8.53 Hz, 2H), 6.35 (dd,J=13.05, 4.77 Hz, 1H), 5.17-5.34 (m, 1H), 4.52 (dt, J=18.63, 4.99 Hz,1H), 4.02 (m, 1H), 3.89 (br d, J=4.27 Hz, 2H), 3.21 (s, 2H), 2.90 (s,3H); LC/MS [M+H]=589.

Example 115 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-((ethoxycarbonyl)amino)benzyl)malonicacid

Step1:

To a solution of diethyl 2-(4-aminobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(1 g, 1.15 mmol, 1 eq.) in Py (20 mL) was added ethyl chloroformate(164.64 uL, 1.73 mmol, 1.5 eq.) at 0° C. The mixture was stirred at 25°C. for 2 hr before the reaction was quenched with H₂O (100 mL). Theaqueous phase was extracted with EtOAc (2×50 mL). The combined organiclayer was washed with brine (50 mL), dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to dryness. The crude product was purified byflash silica gel chromatography (0-20% of ethyl acetate in petroleumether) to provide diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(4-((ethoxycarbonyl)amino)benzyl)malonate(665 mg, 61% yield) as a white foam.

Steps 2-3:

Proceeding as described in Example 2 above from diethyl2-(((2R,3R,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(4-((ethoxycarbonyl)amino)benzyl)malonateto 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-((ethoxycarbonyl)amino)benzyl)malonicacid, the title compound was prepared and isolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 9.49 (s, 1H), 8.27 (d, J=1.76 Hz, 1H), 7.87(br s, 2H), 7.25 (br d, J=8.28 Hz, 2H), 7.11 (d, J=8.53 Hz, 2H), 6.35(dd, J=13.55, 4.77 Hz, 1H), 5.15-5.34 (m, 1H), 4.46-4.56 (m, 1H),3.98-4.05 (m, 2H), 4.05-4.12 (q, J=7.19 Hz, 2H), 3.18 (s, 2H), 1.20-1.24 (t, J=7.2 Hz, 3H); LC/MS [M+H]=583.1.

Example 116 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxopiperidin-1-yl)benzyl)malonicacid

Step1:

To a solution of diethyl 2-(4-aminobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(1 g, 1.15 mmol, 1 eq.) in THF (10 mL) was added TEA (240.72 uL, 1.73mmol, 1.5 eq.) and 5-chlorovaleroyl chloride (178.74 uL, 1.38 mmol, 1.2eq.) at 0° C. The mixture was stirred at 25° C. for 2 hr before themixture was quenched with H₂O (50 mL). The aqueous phase was extractedwith DCM (2×50 mL). The combined organic layer was washed with brine (50mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated todryness. The crude product was purified by flash silica gelchromatography (0-25% of ethyl acetate in petroleum ether) to providediethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(4-(5-chloropentanamido)benzyl)malonate(789 mg, 69% yield) as a white foam.

Steps 2:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)-2-(4-(5-chloropentanamido)benzyl)malonate(789 mg, 800.31 umol, 1 eq.) in DMF (10 mL) was added K₂CO₃ (331.82 mg,2.40 mmol, 3 eq.) at 25° C. The mixture was stirred at 60° C. for 4 hrbefore the reaction was quenched with H₂O (30 mL). The aqueous phase wasextracted with EtOAc (3×20 mL). The combined organic layer was washedwith brine (40 mL), dried over Na₂SO₄ and filtered. The filtrate wasconcentrated to dryness. The crude product was purified by flash silicagel chromatography (0-33% of ethyl acetate in petroleum ether) toprovide diethyl 2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxopiperidin-l-yl)benzyl)malonate(679 mg, 76% yield) as a yellow gum.

Steps 3-4:

Proceeding as described in Example 2 above from provide diethyl 2-4(2R,3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxopiperidin-l-yl)benzyl)malonateto 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxopiperidin-1-yl)benzyl)malonicacid, the title compound was prepared and isolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 14.32-12.09 (br s, 2H), 8.25 (d, J=1.76 Hz,1H), 7.88 (br s, 2H), 7.20 (d, J=8.53 Hz, 2H), 7.01 (d, J=8.28 Hz, 2H),6.35 (dd, J=12.55, 4.77 Hz, 1H), 5.17-5.35 (m, 1H), 4.53 (dt, J=18.63,4.99 Hz, 1H), 4.00 (br d, J=3.76 Hz, 1H), 3.87-3.92 (m, 2H), 3.44-3.49(m, 2H), 3.26 (s, 2H), 2.31-2.37 (m, 2H), 1.74-1.84 (m, 4H); LC/MS[M+H]=593.1.

Example 117 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-iodobenzyl)malonicacid

Proceeding as described in Example 2 above by substituting benzylbromide with 4-iodobenzyl bromide, the title compound was prepared andisolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 8.24 (d, J=2.01 Hz, 1H), 7.88 (br s, 2H),7.49 (d, J=8.28 Hz, 2H), 7.01 (d, J=8.28 Hz, 2H), 6.34 (dd, J=13.18,4.64 Hz, 1H), 5.16-5.34 (m, 1H), 4.46-4.56 (m, 1H), 3.97-4.00 (m, 1H),3.87 (br d, J=4.52 Hz, 2H), 3.20 (s, 2H); LC/MS [M+H]=621.9.

Example 118 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-methoxybenzamido)benzyl)malonicacid

Proceeding as described in Example 113 above by substituting benzoylchloride with 2-methoxylbenzoyl chloride, the title compound wasprepared and isolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 10.02 (s, 1H), 8.30 (d, J=1.25 Hz, 1H),7.88 (br s, 2H), 7.61 (dd, J=7.53, 1.51 Hz, 1H), 7.54 (br d, J=8.53 Hz,2H), 7.43-7.52 (m, 1H) ,7.16 (br d, J=7.28 Hz, 3H), 7.05 (t, J=7.40 Hz,1H), 6.35 (dd, J=13.55, 4.52 Hz, 1H), 5.97-6.13 (m, 1H), 5.14-5.39 (m,1H), 4.45-4.61 (m, 1H), 4.02 (q, J=4.60 Hz, 1H), 3.88 (s, 3H), 3.79-3.87(m, 2H), 3.14-3.22 (s, 2H); LC/MS [M+H]=645.1.

Example 118 Synthesis of 2-(((2R, 3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(thiophene-2-carboxamido)benzyl)malonicacid

Proceeding as described in Example 113 above by substituting benzoylchloride with 2-thiophenecarbonyl chloride, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.31 (d, J=1.75 Hz, 1H), 7.84 (dd, J=3.75, 1Hz, 1H), 7.7 (dd, J=5, 1 Hz, 1H), 7.48 (d, J=8.63 Hz, 2H), 7.28 (d,J=8.63 Hz, 2H), 7.16 (dd, J=5, 3.88 Hz, 1H), 6.43 (dd, J=13.26, 4.38 Hz,1H), 5.25-5.10 (m, 1H) 4.73-4.65 (m, 1H), 4.17 (m, 1H), 4.09-3.95 (m,2H), 3.4 (m, 2H); LC/MS [M+H]=621.1.

Example 119 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2′-carboxy-[1,1′-biphenyl]-4-yl)methyl)malonicacid and 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2′-(ethoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)malonicacid

Step1:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-iodobenzyl)malonate(300 mg, 442.58 umol, 1 eq), 2-ethoxycarbonylphenylboronic acid pinacolester (146.65 mg, 531.09 umol, 1.2 eq) and K₂CO₃ (183.50 mg, 1.33 mmol,3 eq) in 1,4-dioxane (3 mL) and H₂O (1 mL) was added Pd(dppf)Cl₂ (324mg, 442.58 umol, 1 eq) at 20-25° C. under N₂ atmosphere. The reactionmixture was then heated at 80° C. and stirred for 3 hr. The reactionmixture was diluted with H₂O (15 mL), extracted with EtOAc (3×10 mL).The combined organic layer was washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated. The crude was purified by preparativeTLC (50% of ethyl acetate in petroleum ether) to provide diethyl2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2′-(ethoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)malonate(282 mg, 88% yield) as a brownish gum.

Step2:

To a solution of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2′-(ethoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)malonate(100 mg, 142.83 umol, 1 eq) in THF (1 mL) was added LiOH.H₂O (44.95 mg,1.07 mmol, 7.5 eq) in H₂O (0.5 mL) at 20-25° C. The reaction mixture wasstirred at 50° C. for 19 h before it was cooled to room temperature. Thereaction mixture was concentrated and the residue was diluted with H₂O(5mL). The water was wished with EA (3×5mL) and then acidified with 1Naq. HCl until pH reached 2-3. The mixture was then extracted with EtOAc(3×5 mL). The combined organic layer was washed with brine (15 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to provide2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2′-carboxy-[1,1′-biphenyl]-4-yl)methyl)malonicacid (52.2 mg, 56% yield) as a white solid ¹H NMR (CD₃OD, 400 MHz,) δ8.38 (s, 1H), 7.73 (d, J=7.78 Hz, 1H), 7.43-7.54 (m, 1H), 7.35-7.43 (m,1H), 7.31 (d, J=8.03 Hz, 2H), 7.23 (br d, J=7.53 Hz, 1H), 7.15 (d,J=8.03 Hz, 2H), 6.42 (dd, J=13.18, 4.39 Hz, 1H), 5.06-5.28 (m, 1H), 4.69(dt, J=17.44, 4.33 Hz, 1H), 4.18 (m, 1H), 3.90-4.07 (m, 2H), 3.39-3.50(m, 2H); LC/MS [M+H]=616.1.

In a separated reaction, the hydrolysis was carried out for 5 h at roomtemperature provided the ethyl ester.

LC/MS [M+H]=644.2.

Example 120 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((3′-carboxy-[1,1′-biphenyl]-4-yl)methyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonyl phenylboronic acid pinacol ester with3-ethoxycarbonylphenylboronic acid pinacol ester, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.31 (s, 1H), 8.15 (s, 1H), 7.94 (d, J=7.6Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.36-7.44 (m,4H), 6.43 (dd, J=12, 4.8 Hz, 1H), 5.08-5.28 (m, 1H), 4.68 -4.77 (m, 1H),4.16-4.18 (m, 1H), 4.07-4.11 (m, 1H), 3.98 (m, 1H), 3.40-3.52 (m, 2H);LC/MS [M+H]=616.1.

Example 121 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((4′-carboxy-[1,1′-biphenyl]-4-yl)methyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with4-ethoxycarbonylphenylboronic acid pinacol ester, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.33 (s, 1H), 8.03 (m, J=8.28 Hz, 2H), 7.56(m, J=8.28 Hz, 2H), 7.36-7.45 (m, 4H), 6.42 (dd, J=11.92, 4.64 Hz, 1H),5.12-5.25 (m, 1H), 4.73 (dt, J=17.94, 4.58 Hz, 1H), 4.17 (m, 1H),4.03-4.12 (m, 1H), 3.93-4.01 (m, 1H), 3.39-3.51 (m, 2H); LC/MS[M+H]=616.0.

Example 122 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(pyridin-2-yl)benzyl)malonicacid

Proceeding as described in Example 119 above but substituting2-ethoxycarbonylphenylboronic acid pinacol ester with2-(tributylstannyl)pyridine, the title compound was prepared andisolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.58 (br d, J=4.52 Hz, 1H), 8.34 (s, 1H),7.99 (t, J=6.96 Hz, 1H), 7.80 (d, J=8.28 Hz, 1H), 7.71 (br d, J=8.03 Hz,2H), 7.41-7.56 (m, 3H), 6.42 (dd, J=12.55, 4.02 Hz, 1H), 4.97-5.30 (m,1H), 4.60-4.75 (m, 1H), 4.17 (q, J=4.35 Hz, 1H), 3.98-4.05 (m, 1H),3.85-3.98 (m, 1H), 3.34-3.51 (m, 2H); LC/MS [M+H]=573.1.

Example 123 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(pyridin-3-yl)benzyl)malonic acid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with 3-pyridyl boronicacid pinacol ester, the title compound was prepared and isolated as awhite solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 8.84 (br s, 1H), 8.56 (br d, J=4.00 Hz,1H), 8.27 (d, J=1.63 Hz, 1H), 8.01 (br d, J=8.00 Hz, 1H), 7.87 (br s,2H), 7.46-7.54 (m, 3H), 7.34 (d, J=8.13 Hz, 2H), 6.36 (dd, J=13.13, 4.75Hz, 1H), 6.06 (br s, 1H), 5.17-5.36 (m, 1H), 4.49-4.60 (m, 1H), 4.03 (q,J=4.92 Hz, 1H), 3.90 (br d, J=4.38 Hz, 2H), 3.31 (s, 2H); LC/MS[M+H]=573.

Example 124 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(pyridin-4-yl)benzyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with 4-pyridyl boronicacid pinacol ester, the title compound was prepared and isolated as awhite solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 8.64 (d, J=6.02 Hz, 2H), 8.28 (d, J=1.76Hz, 1H), 7.88 (br s, 2H), 7.69 (br d, J=4.77 Hz, 2H), 7.60 (d, J=8.03Hz, 2H), 7.36 (d, J=8.28 Hz, 2H), 6.36 (dd, J=13.18, 4.64 Hz, 1H), 6.07(br s, 1H), 5.14-5.38 (m, 1H), 4.55 (br d, J=18.82 Hz, 1H), 4.00-4.03(m, 1H), 3.90 (br s, 2H), 3.32 (br s, 2H); LC/MS [M+H]=573.1.

Example 125 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(pyrimidin-5-yl)benzyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with 4-pyrimidinylboronic acid pinacol ester, the title compound was prepared and isolatedas a white solid.

¹HNMR (DMSO-d₆, 400 MHz,) δ 9.16 (s, 1H), 9.08 (s, 2H), 8.28 (s, 1H),7.86 (br s, 2H), 7.63 (br d, J=8.00 Hz, 2H), 7.36 (br d, J=7.88 Hz, 2H),6.36 (br dd, J=13.07, 4.57 Hz, 1H), 6.05 (br s, 1H), 5.14-5.37 (m, 1H),4.55 (br d, J=18.39 Hz, 1H), 4.03 (br d, J=4.13 Hz, 1H), 3.86 (br s,2H), 3.30 (s, 2H); LC/MS [M+H]=574.1.

Example 126 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(5-methyl-1H-pyrazol-4-yl)benzyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with5-methylpyrazole-4-boronic acid pinacol ester, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.38 (s, 1H) 7.61 (s, 1H) 7.27-7.37 (d, J=8,2H) 7.18-7.26 (d, J=8, 2H) 6.42 (dd, J=13.18, 4.39 Hz, 1H) 5.08-5.28 (m,1H) 4.66-4.78 (m, 1H) 4.17 (br d, J=4.77 Hz, 1H) 3.88-4.05 (m, 2H) 3.40(s, 2H) 2.32 (s, 3H); LC/MS [M+H]=576.

Example 127 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(3,5-dimethyl-1H-pyrazol-4-yl)benzyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with3,5-dimethylpyrazole-4-boronic acid pinacol ester, the title compoundwas prepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.37 (d, J=1.76 Hz, 1H), 7.34 (d, J=8.03 Hz,2H), 7.10 (d, J=8.03 Hz, 2H), 6.41 (dd, J=13.68, 4.39 Hz, 1H), 4.91-5.24(m, 1H), 4.68 (br d, J=18.32 Hz, 1H), 4.17 (br d, J=4.27 Hz, 1H),3.94-4.04 (m, 2H), 3.34-3.45 (m, 2H), 2.25 (s, 6H); LC/MS [M+H]=589.9.

Example 128 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(3,5-dimethylisoxazol-4-yl)benzyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with3,5-dimethylisoxazole-4-boronic acid pinacol ester, the title compoundwas prepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.33 (s, 1H), 7.39 (d, J=7.38 Hz, 2H), 7.13(d, J=7.75 Hz, 2H), 6.41 (dd, J=13.45, 4.57 Hz, 1H), 5.01-5.25 (m, 1H),4.67 (dt, J=17.85, 4.14 Hz, 1H), 4.16 (br d, J=4.75 Hz, 1H), 3.88-4.09(m, 2H), 3.39-3.50 (m, 2H), 2.31 (s, 3H), 2.16 (s, 3H); LC/MS [M+H]=591.

Example 129 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(thiophen-2-yl)benzyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with2-thiophene-2-boronic acid pinacol ester, the title compound wasprepared and isolated as a white solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.30 (d, J=1.75 Hz, 1H), 7.88 (br s, 2H),7.51 (d, J=5.13 Hz, 1H), 7.40-7.47 (m, 3H), 7.24 (d, J=8.25 Hz, 2H),7.11 (dd, J=5.00, 3.63 Hz, 1H), 6.36 (dd, J=13.38, 4.63 Hz, 1H), 6.06(br s, 1H), 5.17-5.37 (m, 1H), 4.55 (br d, J=19.76 Hz, 1H), 3.99-4.06(m, 1H), 3.88 (br s, 2H), 3.26 (s, 2H); LC/MS [M+H]=578.

Example 130 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)methyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with4-(methanesulfonylphenyl)-boronic acid pinacol ester, the title compoundwas prepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.27 (d, J=1.50 Hz, 1H), 7.92-7.96 (m, 2H),7.68-7.72 (m, 2H), 7.41 (q, J=8.42 Hz, 4H), 6.41 (dd, J=11.26, 4.88 Hz,1H), 5.11-5.25 (m, 1H), 4.69-4.84 (m, 1H), 4.07-4.18 (m, 2H), 3.95 (dd,J=10.32, 4.06 Hz, 1H), 3.40-3.55 (m, 2H), 3.31 (s, 3H); LC/MS[M+H]=650.1.

Example 131 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((4′-fluoro-[1,1′-biphenyl]-4-yl)methyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with4-fluorophenyl-boronic acid pinacol ester, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.34 (d, J=1.00 Hz, 1H), 7.39-7.46 (m, 2H),7.27-7.37 (m, 4H), 7.07 (t, J=8.78 Hz, 2H), 6.42 (dd, J=11.54, 4.77 Hz,1H) 5.08-5.30 (m, 1H), 4.73 (dt, J=18.01, 4.93 Hz, 1H), 4.13-4.20 (m,1H), 4.09 (br d, J=10.29 Hz, 1H), 3.96 (dd, J=10.04, 4.27 Hz, 1H),3.38-3.51 (m, 2H); LC/MS [M+H]=590.4.

Example 132 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-aminopyrimidin-5-yl)benzyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with2-aminopyrimidine-5-boronic acid pinacol ester, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.45 (s, 2H), 8.29 (s, 1H), 7.34 (q, J=8.28Hz, 4H), 6.41 (dd, J=12.55, 4.52 Hz, 1H), 5.04-5.25 (m, 1H), 4.70 (dt,J=17.82, 4.77 Hz, 1H), 4.16 (q, J=4.43 Hz, 1H), 4.03 (br dd, J=9.91,3.39 Hz, 1H), 3.94 (dd, J=9.66, 4.64 Hz, 1H), 3.33-3.49 (m, 2H); LC/MS[M+H]=589.

Example 132 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2′-hydroxy-[1,1′-biphenyl]-4-yl)methyl)malonicacid

Proceeding as described in Example 119 above by substituting2-ethoxycarbonylphenylboronic acid pinacol ester with2-hydroxyphenyl-boronic acid pinacol ester, the title compound wasprepared and isolated as a white solid.

¹H NMR (DMSO-d6, 400 MHz,) δ 9.47 (s, 1H), 8.29 (s, 1H), 7.89 (br s,2H), 7.35 (d, J=8.28 Hz, 2H), 7.24 (d, J=8.03 Hz, 2H), 7.08-7.17 (m,2H), 6.91 (d, J=7.53 Hz, 1H), 6.82-6.87 (m, 1H), 6.36 (dd, J=13.80, 4.77Hz, 1H), 6.05 (br s, 1H), 5.16-5.37 (m, 1H), 4.51-4.62 (m, 1H),4.00-4.03 (m, 1H), 3.90 (m, 2H), 3.27 (s, 2H); LC/MS [M+H]=588.1.

Example 133 Synthesis of 2-(((2R, 3S, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid

Step1:

To a solution of(2R,3S,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-2-(((4-methoxyphenyl)diphenylmethoxy)methyl)tetrahydrofuran-3-yl 4-nitrobenzoate (930 mg, 1.01 mmol, 1 eq) in DCM (5mL) was added TFA (0.6 mL, 8.10 mmol, 8.06 eq) in DCM (5 mL) at 0° C.The reaction mixture was stirred at 0° C. for 0.1 h. The reactionmixture was basified by TEA until pH reached ˜7 and then concentrated.The crude was purified by column chromatography on silica gel (elutedwith 0-33% of EtOAc in petroleum ether) to provide(2R,3S,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl4-nitrobenzoate (480 mg, 66% yield) as a brownish foam.

Step2:

To a solution of the alcohol product from the previous step (480 mg,735.06 umol, 1 eq) and Rh₂(OAc)₄ (32.49 mg, 73.51 umol, 0.1 eq) intoluene (4.8 mL) was added diethyl 2-diazomalonate (246.31 mg, 1.32mmol, 1.8 eq) in toluene (2.4 mL) under N₂ at 90° C. The reactionmixture was stirred at 90° C. for 4 h. The reaction mixture wasconcentrated to dryness. The crude was purified by column chromatographyon silica gel (eluted with 0-30% of EtOAc in petroleum ether) to providediethyl2-(((2R,3S,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-((4-nitrobenzoyl)oxy)tetrahydrofuran-2-yl)methoxy)malonate(250 mg, 39% yield) was obtained as a brownish gum.

Step3:

To a solution of diethyl2-(((2R,3S,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-((4-nitrobenzoyl)oxy)tetrahydrofuran-2-yl)methoxy)malonate (250 mg, 308.20 umol, 1 eq) andK₂CO₃ (85.19 mg, 616.40 umol, 2 eq) in DMF (2.5 mL) was stirred at20-25° C. for 1 h. The reaction mixture was added methyl(4-bromomethyl)benzoate (141.20 mg, 616.40 umol, 2 eq) and stirred at20-25° C. for 16 hr. The reaction mixture diluted with H₂O (20 mL),extracted with EtAOc (3×10 mL). The combined organic layer was washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated. Thecrude was purified by preparative TLC (eluted with 33% of EtOAc inpetroleum ether) to provide diethyl2-(((2R,3S,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-((4-nitrobenzoyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate(170 mg, 56% yield) as a colorless gum.

Step4:

To a solution of diethyl2-(((2R,3S,4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-((4-nitrobenzoyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate (170mg, 177.21 umol, 1 eq) in DCM (2 mL) was added TFA (462.00 mg, 4.05mmol, 0.3 mL, 22.86 eq) at 0° C. The reaction mixture was stirred at20-25° C. for 1 h. The reaction mixture was cooled to 0° C. and basifiedby TEA until pH reached ˜7. The mixture was then concentrated. The crudewas purified by preparative TLC (eluted with 50% of EtOAc in petroleumether) to provide diethyl2-(((2R,3S,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-((4-nitrobenzoyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate (125 mg, 93% yield) as acolorless gum.

Step5:

To a solution of diethyl2-(((2R,3S,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-((4-nitrobenzoyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate (125 mg, 164.67 umol, 1eq) in THF (1.2 mL) was added LiOH.H₂O (69.10 mg, 1.65 mmol, 10 eq) inH₂O (0.7 mL) at 20-25° C. The reaction mixture was stirred at 50° C. for2 h. The reaction mixture was quenched with H₂O (20 mL) andconcentrated. The aq. layer was wished with EtOAc (3×15mL) and thenacidified with 1N aq. HCl until the pH reached 2-3 as white solidformed. The mixture was filtered and the solid was collected and driedto provide2-(((2R,3S,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid (44.9 mg, 49% yield) as a white solid.

¹H NMR (DMSO-d₆, 400 MHz,) δ 12.82 (br s, 2H), 8.29 (s, 1H), 7.89 (br s,2H), 7.75 (d, J=8.03 Hz, 2H), 7.28 (br d, J=7.53 Hz, 2H), 6.34 (dd,J=14.31, 4.52 Hz, 1H), 6.06 (br s, 1H), 5.12-5.34 (m, 1H), 4.52 (br d,J=18.07 Hz, 1H), 4.00 (br d, J=4.77 Hz, 1H), 3.76 (br s, 2H), 3.23 (brs, 2H); LC/MS [M+H]=540.

Example 134 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxopyrrolidin-1-yl)benzyl)malonicacid

Proceeding as described in Example 116 above by substituting5-chlorovaleroyl chloride with 4-chlorobutyryl chloride, the titlecompound was prepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.26 (s, 1H), 7.32-7.39 (d, J=8.4 Hz, 2H),7.22-7.31 (d, J=8.4 Hz, 2H), 6.42 (dd, J=11.80, 4.77 Hz, 1H), 5.09-5.27(m, 1H), 4.70 (br d, J=17.32 Hz, 1H), 4.14 (br d, J=5.02 Hz, 1H),4.03-4.10 (m, 1H), 3.94 (m, 1H), 3.65-3.83 (m, 2H), 3.39 (br d, J=9.03Hz, 2H), 2.55 (t, J=8.16 Hz, 2H), 2.07-2.19 (m, 2H); LC/MS [M+H]=579.

Example 135 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(1,1-dioxido-1,2-thiazinan-2-yl)benzyl)malonicacid

Proceeding as described in Example 116 above by substituting5-chlorovaleroyl chloride with 4-chloro-1-butanesulfonyl chloride, thetitle compound was prepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.32 (s, 1H), 7.29 (d, J=8.53 Hz, 2H), 7.11(d, J=8.28 Hz, 2H), 6.41 (dd, J=12.80, 4.52 Hz, 1H), 5.05-5.27 (m, 1H),4.66 (dt, J=18.01, 4.42 Hz, 1H), 4.15 (q, J=4.35 Hz, 1H), 3.92-4.05 (m,2H), 3.54-3.65 (m, 2H), 3.47-3.49 (m, 2H), 3.13-3.27 (m, 2H), 2.21-2.29(m, 2H), 1.78-1.88 (m, 2H); LC/MS [M+H]=629.

Example 136 Synthesis of 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)malonicacid

Step1:

To a mixture of diethyl 2-(4-aminobenzyl)-2-(((2R, 3R, 4S,5R)-5-(6-(N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-fluorotetrahydrofuran-2-yl)methoxy)malonate(300 mg, 345 umol, 1 eq) in THF (3 mL) was added1-chloro-3-isocyanatopropane (53.8 mg, 449 umol, 1.3 eq). The mixturewas stirred at 25° C. for 17 hours before it was quenched with H₂O (10mL). The aqueous phase was extracted with EA (2×20 mL). The combinedorganic layer was washed with brine (10 mL), dried over Na₂SO₄ andfiltered. The filtrate was concentrated to dryness and purified by flashsilica gel chromatography (0-50% of EtOAc in petroleum ether) to givethe urea product (260 mg, 76% yield) as a colorless gum.

Step2:

To a mixture of the urea product isolated from the previous step (260mg, 263 umol, 1 eq) in DMF (8 mL) was added Cs₂CO₃ (343 mg, 1.05 mmol, 4eq). The mixture was stirred at 50° C. for 2 hours before it wasquenched with H₂O (20 mL). The aqueous phase was extracted with EA (2×20mL). The combined organic layer was washed with brine (20 mL), driedover Na₂SO₄ and filtered. The filtrate was concentrated to dryness. Thecrude product was purified by flash silica gel chromatography (0-100% ofEtOAc in petroleum ether) to give the cyclized urea product (150 mg, 58%yield) as a colorless gum.

Step3:

To a mixture of the cyclized urea product from the previous step (150mg, 158 umol, 1 eq) in DCM (2 mL) was added TFA (882 uL, 11.9 mmol, 75.5eq). The mixture was stirred at 25° C. for 3 hours before it wasquenched with saturated aq. NaHCO₃ (5 ml), then extracted with EA (2×30mL). The combined extracts were washed with brine (2×10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a crude product. The mixture was purified by preparative TLC (1%MeOH in EtOAc) to give diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)malonate(60 mg, 58% yield) as a white solid.

Step4:

To a mixture of diethyl 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)malonate(90 mg, 138 umol, 1 eq) in THF (2 mL) was added LiOH.H₂O (84 mg, 2.00mmol, 1 mL, 14.4 eq). The mixture was stirred at 20° C. for 17 hoursbefore the mixture was partitioned between EtOAc (10 mL) and water (10mL). The aqueous phase was adjusted to pH to 2-3 with 2M aq. HClsolution. The aqueous phase was partitioned between EtOAc (40 mL) andbrine (20 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a crudeproduct. The mixture was lyophilized to give 2-(((2R, 3R, 4S,5R)-5-(6-amino-2-methyl-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)malonicacid (51.2 mg, 59% yield) as a white powder.

¹H NMR (CD₃OD, 400 MHz,) δ 8.37 (d, J=1.25 Hz, 1H), 7.28 (d, J=8.28 Hz,2H), 7.05 (d, J=8.53 Hz, 2H), 6.42 (dd, J=12.05, 4.52 Hz, 1H), 5.08-5.31(m, 1H), 4.58-4.73 (m, 1H), 4.11-4.18 (m, 1H), 3.92-4.06 (m, 2H), 3.53(t, J=5.65 Hz, 2H), 3.35-3.46 (m, 2H), 3.47-3.33 (m, 2H), 1.90-2.04 (m,2H); LC/MS [M+H]=594.

Example 137 Synthesis of2-(((2S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid

Step1:

To a mixture of diethyl2-(((2R,3R,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate(70 mg, 112.18 umol, 1 eq) in MeCN (2 mL) was added TCDI (29.99 mg,168.27 umol, 1.5 eq) at 20° C. The mixture was stirred at 20° C. for 17hours. Additional amount of TCDI (29.99 mg, 168.27 umol, 1.5 eq) wasadded into the above mixture, and the mixture was stirred at 20° C. for3 hours. The mixture was partitioned between EtOAc (20 mL) and water (10mL), the aqueous phase was extracted with EtOAc (3×10 mL). The combinedextracts were washed with brine (2×20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give diethyl2-(((2R, 3R, 4R,5R)-3-((1H-imidazole-1-carbonothioyl)oxy)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate(75 mg) as yellow oil. The crude product was used in next step withoutpurification.

Step2:

A mixture of the product isolated from the previous step (150 mg, 204.32umol, 1 eq) and AIBN (3.36 mg, 20.43 umol, 0.1 eq) in toluene (5 mL),the mixture was heated at 110° C., and then n-Bu₃SnH (89.20 mg, 306.48umol, 81.09 uL, 1.5 eq) was added to the above mixture. The mixture wasstirred at 110° C. for 0.5 hour. The mixture was cooled to roomtemperature and quenched with saturated aq. KF (8 mL), extracted withEtOAc (3×15 mL), the combined extracts was washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue, which was purified by flash silica gelchromatography (0-60% of EtOAc in petroleum ether) to give diethyl2-4(2S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl) benzyl)malonate (65 mg,104.77 umol, 51.28% yield, 98% purity) as white gum.

Step3:

To a mixture of diethyl 2-(((2S, 4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonate (60 mg, 98.68 umol, 1 eq) in THF (2 mL) was addedLiOH.H₂O (82.82 mg, 1.97 mmol, 20 eq) in H₂O (2 mL). The mixture wasstirred at 25° C. for 20.5 hours. The reaction mixture was adjusted thepH to 2-3 with 2M aq. HCl, then extracted with EtOAc (3×50 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give a crude product which was purified by preparative reversed-phaseHPLC and was lyophilized to give2-(((2S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonicacid (11.1 mg, 21% yield) as a white powder.

¹H NMR (DMSO-d₆, 400 MHz,) δ 12.79 (br s, 1H), 8.52 (s, 1H), 7.87 (br s,2H), 7.73 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 6.11 (d, J=16.8 Hz,1H), 4.43-4.64 (m, 1H), 3.94-4.05 (m, 1H), 3.81-3.88 (m, 1H), 3.35 (s,2H), 2.32-2.37 (m, 2H), 1.07-1.18 (d, J=22.0 Hz, 3H); LC/MS [M+H]=538.

Example 138 Synthesis of 2-(((2S,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxy-3-methyltetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Proceeding as described in Example 2 above, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.65 (s, 1H), 7.19-7.30 (m, 2H), 7.08-7.16(m, 3H), 5.97 (s, 1H), 4.29 (d, J=4.52 Hz, 1H), 4.17 (d, J=9.29 Hz, 2H),3.73-3.84 (m, 1H), 3.39-3.52 (m, 2H), 2.62 (m, 1H), 1.03 (d, J=6.78 Hz,3H); LC/MS [M+H]=492.

Example 139 Synthesis of2-(((2S,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxy-3-methyltetrahydrofuran-2-yl)methoxy)-2-benzylmalonicacid

Proceeding as described in Example 2 above, the title compound wasprepared and isolated as a white solid.

¹H NMR (CD₃OD, 400 MHz,) δ 8.34 (s, 1H), 7.19 (br d, J=6.78 Hz, 2H),6.99-7.09 (m, 3H), 5.78 (d, J=7.28 Hz, 1H), 4.59 (m, 1H), 4.40 (br d,J=8.53 Hz, 1H), 3.94 (br d, J=9.03 Hz, 1H), 3.66-3.72 (m, 1H), 3.45-3.52(m, 1H), 3.33-3.39 (m, 1H), 2.51-2.58 (m, 1H), 1.14 (d, J=6.78 Hz, 3H);LC/MS [M+H]=492.

Example 140 Synthesis of (S)-2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(1H-tetrazol-5-yl)-3-(4-(trifluoromethoxy)phenyl)propanoic acid

Proceeding as described in Example 80 above, but substituting benzylbromide with 4-(trifluoromethoxy)benzyl bromide, the title compound wasprepared and isolated as a solid mixture of diastereomers (ca.1:1ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio):

Isomer 1: δ 8.37 (bs, 1H), 7.19 (d, J=8.35 Hz, 2H), 6.96 (d, J=8.11 Hz,2H), 5.99 (d, J=5.79 Hz, 1H), 4.71 (t, J=5.12 Hz, 1H), 4.40 (t, J=4.37Hz, 1H), 4.31-4.20 (m, 1H), 3.98-3.89 (m, 1H), 3.86-3.64 (m, 3H); LC/MS[M+H]=602.

Isomer 2: δ 8.40 (bs, 1H), 7.19 (d, J=8.35 Hz, 2H), 7.07 (d, J=7.99 Hz,2H), 5.98 (d, J=5.67 Hz, 1H), 4.80 (t, J=5.15 Hz, 1H), 4.45 (t, J=4.17Hz, 1H), 4.31-4.20 (m, 1H), 3.98-3.89 (m, 1H), 3.86-3.64 (m, 3H); LC/MS[M+H]=602.

Example 141 Synthesis of4-(2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-carboxy-2-(1H-tetrazol-5-yl)ethyl)benzoicacid

Proceeding as described in Example 79 above, but substituting thetetra-Boc protected alcohol described in Example 77 forN6,N6-bis-Boc-2′-3′-O-isopropylidene-2-chloro-adenosine provided theRh-catalyzed insertion product. The subsequent deprotecting procedure asdescribed in Example 80 above, but substituting benzyl bromide withmethyl-4-(bromomethyl)benzoate, the title compound was prepared andisolated as a solid mixture of diastereomers (ca.3:2 ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.3:2 ratio):Minor isomer: δ 8.35 (s, 1H), 7.81 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.14Hz, 2H), 5.98 (d, J=5.1 Hz, 1H), 4.72 (t, J=5.1 Hz, 1H), 4.41 (t, J=4.29Hz, 1H), 4.32-4.22 (m, 1H), 4.03-3.67 (m, 4H); LC/MS [M+H]=562.

Major isomer: δ 8.38 (s, 1H), 7.70 (d, J=8.23 Hz, 2H), 7.20 (d, J=8.13Hz, 2H), 6.01 (d, J=5.34 Hz, 1H), 4.79 (t, J=5.15 Hz, 1H), 4.46 (t,J=4.38 Hz, 1H), 4.32-4.22 (m, 1H), 4.03-3.67 (m, 4H); LC/MS [M+H]=562.

Example 142 Synthesis of2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-(4-(benzyloxy)phenyl)-2-(1H-tetrazol-5-yl)propanoicacid

Proceeding similarly to that described in Example 80 above, butsubstituting benzyl bromide with 4-(benzyloxy)benzyl bromide, the titlecompound was prepared and isolated as a solid mixture of diastereomers(ca. 3:2 ratio).

NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.3:2 ratio):

Minor isomer: δ 8.41 (bs, 1H), 7.41-7.21 (M, 5H),7.01-6.91(m, 2H),6.83-6.62 (m, 2H), 6.01 (d, J=5.25 Hz, 1H), 4.90-4.86 (bs, 2H), 4.76 (t,J=4.89 Hz, 1H), 4.49-4.44 (m, 1H), 4.30-4.25 (m, 1H), 4.0-3.85 (m, 1H),3.79-3.51 (m, 2H), 3.26-3.15 (m, 1H); LC/MS [M+H]=624.

Major isomer: δ 8.32 (bs, 1H), 7.41-7.21 (M, 5H),7.01-6.91(m, 2H),6.83-6.62 (m, 2H), 5.97 (d, J=5.16 Hz, 1H), 4.90-4.86 (bs, 2H), 4.69 (t,J=4.74 Hz, 1H), 4.49-4.44 (m, 1H), 4.30-4.25 (m, 1H), 4.0-3.85 (m, 1H),3.79-3.51 (m, 2H), 3.26-3.15 (m, 1H); LC/MS [M+H]=624.

Example 143 Synthesis of2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(1H-tetrazol-5-yl)-3-(3-(trifluoromethoxy)phenyl)propanoicacid

Proceeding similarly to that described in Example 80 above, butsubstituting benzyl bromide with 3-(trifluoromethoxy)benzyl bromide, thetitle compound was prepared and isolated as a solid mixture ofdiastereomers (ca.3:2 ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.3:2 ratio):

Minor isomer: δ 8.42 (bs, 1H), 7.35-6.94 (M, 4H), 6.01 (d, J=5.16 Hz,1H), 4.80-4.75 (m, 1H), 4.44 (t, J=4.24 Hz, 1H), 4.32-4.22 (m, 1H),3.99-3.87 (m, 1H), 3.83-3.67 (m, 3H); LC/MS [M+H]=601.

Major isomer: δ 8.42 (bs, 1H), 7.35-6.94 (M, 4H), 5.98 (d, J=4.92 Hz,1H), 4.72(t, J=4.91 Hz, 1H), 4.40 (t, J=4.47 Hz, 1H), 4.32-4.22 (m, 1H),3.99-3.87 (m, 1H), 3.83-3.67 (m, 3H); LC/MS [M+H]=601.

Example 144 Synthesis of2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoicacid

Proceeding similarly to that described in Example 80 above, butsubstituting benzyl bromide with 4-(benzyloxy)benzyl bromide, the titlecompound was prepared and isolated as a solid mixture of diastereomers(ca.1:1 ratio).

LC/MS [M+H]=520.

Example 145 Synthesis of4′-(2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-carboxy-2-(2H-tetrazol-5-yl)ethyl)-[1,1′-biphenyl]-2-carboxylicacid

Step1:

To a solution of ethyl 1H-tetrazole-5-acetate (3 g, 19.21 mmol) in DMF(40 mL) under argon atmosphere was added 2-(trimethylsilyl)ethoxymethylchloride (4.1 mL, 23.05 mmol) and powdered potassium carbonate (5.31 g,38.42 mmol). The reaction mixture was stirred overnight. Brine (70 mL)and EtOAc (70 mL) were added and the mixture was shaken and the organicphase isolated. The aqueous phase was extracted with EtOAc (2×70 mL).The combined organic layer was washed consecutively with brine (70 mL)and water (70 mL) and then dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography (15-48% EtOAcin hexanes) to provide ethyl2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl]acetate (2.379g) as a light yellow mobile oil.

Step2:

To a solution of ethyl2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl]acetate (2.379g, 8.31 mmol) in dry acetonitrile (25 mL) under argon atmosphere wasadded DBU (1.87 mL, 12.47 mmol) and followed by4-acetamidobenzenesulfonyl azide (2.395 g, 9.96 mmol) in 3 equalportions over 5 minutes. The reaction mixture was stirred for 3.5 hoursand then the solvent was removed (rotary evaporator). The residue waspurified by silica gel column chromatography (20% EtOAc in hexanes) toprovide ethyl 2-diazo-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)acetate (2.316 g) as a light orangethick oil.

Steps 4-6:

Proceeding similarly to that described in Example 77 above, butsubstituting diethyl 2-diazomalonate with ethyl2-diazo-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl]acetateand also substituting methyl-4-(bromomethyl)benzoate with methyl4′-bromomethyl biphenyl-2-carboxylate, the title compound was preparedand isolated as a solid mixture of diastereomers (ca.1:1 ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio):

Isomer 1: δ 8.52 (s, 1H), 7.77 (d, J=6.18 Hz, 1H), 7.54-7.07 (m, 7H),6.05 (d, J=5.76 Hz, 1H), 4.82 (t, J=5.34 Hz, 1H), 4.44-4.38 (m, 1H),4.31-4.27 (m, 1H), 4.09-3.90 (m, 1H), 3.86-3.60 (m, 3H); LC/MS[M+H]=638.

Isomer 2: δ 8.39 (s, 1H), 7.76 (d, J=6.33 Hz, 1H), 7.54-7.07 (m, 7H),5.99 (d, J=5.61 Hz, 1H), 4.70 (t, J=5.25 Hz, 1H), 4.42-4.38 (m, 1H),4.28-4.23 (m, 1H), 4.09-3.90 (m, 1H), 3.86-3.60 (m, 3H); LC/MS[M+H]=638.

Example 146 Synthesis of4-(2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-carboxy-2-(1H-tetrazol-5-yl)ethyl)thiophene-2-carboxylicacid

Proceeding similarly to that described in Example X10 above, butsubstituting 3-(trifluoromethoxy)benzyl bromide with methyl4-(bromomethyl)thiophene-2-carboxylate, the title compound was preparedand isolated as a solid mixture of diastereomers (ca.1:1 ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio):

Isomer 1: δ 8.46 (s, 1H), 7.53 (bs, 1H), 7.38 (bs, 1H), 6.00 (d, J=4.98Hz, 1H), 4.74 (t, J=5.12 Hz, 1H), 4.44 (t, J=4.25 Hz, 1H), 4.34-4.24 (m,1H), 4.03-3.90 (m, 1H), 3.83-3.69 (m, 3H); LC/MS [M+H]=568.

Isomer 2: δ 8.49 (s, 1H), 7.58 (bs, 1H), 7.40 (bs, 1H), 6.04 (d, J=5.37Hz, 1H), 4.81 (t, J=5.12 Hz, 1H), 4.39 (t, J=4.49 Hz, 1H), 4.34-4.24 (m,1H), 4.03-3.90 (m, 1H), 3.83-3.69 (m, 3H); LC/MS [M+H]=568.

Example 147 Synthesis of2-(((2R,3R,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(2H-tetrazol-5-yl)propanoicacid

Proceeding as described in Example 145 above, but substitutingtert-butyl-(tertbutoxycarbonyl)(9-((2R,3R,4R,5R)-3,4-bis((tert-butoxycarbonyl)oxy)-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamatefortert-butyktert-butoxycarbonyl)(9-((2R,3R,4R,5R)-3,4-bis((tert-butoxycarbonyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate and alsosubstituting methyl 4′-bromomethyl biphenyl-2-carboxylate with benzylbromide, the title compound was prepared and isolated as a solid mixtureof diastereomers (ca.1:1 ratio).

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.3:2 ratio):

Minor isomer: δ 8.47 (bs, 1H), 7.19-6.96 (M, 5H), 6.015 (bs, 1H), 4.33(d, J=9.07 Hz, 1H), 4.25-4.16 (m, 1H), 4.13-3.67 (m, 4H), 0.98 (bs, 3H);LC/MS [M+H]=532.

Major isomer: δ 8.48 (bs, 1H), 7.19-6.96 (M, 5H), 6.04 (bs, 1H), 4.39(d, J=9.04 Hz, 1H), 4.25-4.16 (m, 1H), 4.13-3.67 (m, 4H), 0.98 (bs, 3H);LC/MS [M+H]=532.

Example 148a and 148b Synthesis of2-(((2R,3R,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(2H-tetrazol-5-yl)propanoicacid and2-(((2R,3R,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(2-(tert-butyl)-2H-tetrazol-5-yl)-3-phenylpropanoicacid

Step1:

To a solution of tert-butyl(9-((2R,3R,4S,5R)-4-((N-(tert-butoxycarbonyl)(tert-butoxyl)amino)-3-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-chloro-9H-purin-6-yl)carbamate(622 mg, 0.868 mmol) in dry toluene (3 mL) was added ethyl2-diazo-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)acetate(353 mg, 1.13 mmol) and the flask was evacuated and back filled withargon. Rh₂(OAc)₄ (8 mg, 0.017 mmol) was added and the flask was againevacuated and back-filled with argon. The resulting mixture was stirredat 75° C. for 2.5 hours before it was allowed to cool to roomtemperature. The crude mixture was purified by silica gel columnchromatography (5-55% EtOAc in hexanes) to provide the diastereomericmixture of ethyl2-(((2R,3S,4R,5R)-5-(6-(N,N′-bis(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)acetate(757 mg) as an oil.

Step2:

To a solution of diastereomeric mixture of ethyl2-(((2R,3S,4R,5R)-5-(6-(N,N′-bis(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)acetate(757 mg, 0.756 mmol) in dry DMF (5 mL) was added Cs₂CO₃ (1.23 g, 3.78mmol) and BnBr (207 mg, 1.21 mmol). The reaction mixture was stirred for3 hours. Diluted brine solution (25 mL) was added and the material wasextracted with EtOAc (3×25 mL). The combined organic layer was washedfurther with brine (25 mL), dried over Na₂SO₄ and concentrated. Theresulting crude was purified by silica gel column chromatography (5-60%EtOAc in hexanes) to provide ethyl2-(((2R,3S,4R,5R)-5-(6-(N,N′-bis-(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)propanoateas a mixture of diastereomers (ca.1:1 ratio).

Step3:

Ethyl2-(((2R,3S,4R,5R)-5-(6-(N,N′-bis-(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)propanoate(551 mg, 0.505 mmol) was dissolved in dry THF (8 mL) and to this mixturewas added a solution of TBAF (1.16 mL, 1.16 mmol, 1 M in THF) dropwise.The reaction mixture was stirred 1 hour before it was evaporated todryness. The remainder was purified by silica gel column chromatography(8-60% EtOAc in hexanes) to provide ethyl2-(((2R,3R,4R,5R)-5-(6-(N,N′-bis-(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-hydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)propanoate(169 mg) as a viscous clear oil.

Steps 4-5:

Proceeding similarly to that described in Example 2 above, the ethyl2-(((2R,3R,4R,5R)-5-(6-(N,N′-bis-(tert-butoxycarbonyl)-2-chloro-9H-purin-9-yl)-3-((tert-butoxycarbonyl)oxy)-4-hydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)propanoatewas converted to the title diastereomeric compounds, 148a and 148b andisolated as light brown solids.

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio)for Example X13a:

Isomer 1: δ 8.29 (bs, 1H), 7.22-7.16 (M, 2H), 7.15-7.05 (m, 2H),7.03-6.98 (m, 1H), 5.98 (bs, 1H), 4.61-4.49 (m, 1H), 4.47 (bs, 1H),4.27-4.18 (m, 1H), 4.13-4.02 (m, 1H), 3.08 (dd, J=8.29, 8.29 Hz, 1H)3.74-3.55 (m, 2H); LC/MS [M+H]=518.

Isomer 2: δ 8.23 (bs, 1H), 7.22-7.16 (M, 2H), 7.15-7.05 (m, 2H),7.03-6.98 (m, 1H), 5.95 (bs, 1H), 4.61-4.49 (m, 1H), 4.39 (bs, 1H),4.27-4.18 (m, 1H), 4.13-4.02 (m, 1H), 3.95 (dd, J=5.06, 9.44 Hz, 1H)3.74-3.55 (m, 2H); LC/MS [M+H]=518.

¹H NMR (CD₃OD, 300 MHz) for a mixture of diastereomers (ca.1:1 ratio)for Example X13b: Isomer 1: 8 8.25 (bs, 1H), 7.35-7.16 (M, 5H), 5.91(bs, 1H), 4.46-4.36 (m, 2H), 4.18-4.11 (m, 1H), 4.03-3.91 (m, 1H),3.85-3.75 (m, 1H), 3.72-3.53 (m, 2H), 1.73 (s, 9H); LC/MS [M+H]=574.

Isomer 2: δ 8.18 (bs, 1H), 7.35-7.16 (M, 5H), 5.90 (bs, 1H), 4.46-4.36(m, 2H), 4.18-4.11 (m, 1H), 4.03-3.91 (m, 1H), 3.85-3.75 (m, 1H),3.72-3.53 (m, 2H), 1.72 (s, 9H); LC/MS [M+H]=574.

Example 149 Inhibition of the CD73 Enzyme In Vitro

For measurements of soluble CD73 enzyme activity, recombinant CD73 wasobtained from R&D Systems, Cat. No. 5795-EN-010. Serial dilutions oftest compounds were incubated with recombinant CD73 and AMP in reactionbuffer (25 mM Tris HCl pH7.5, 5 mM MgCl2, 50 mM NaCl, 0.25 mM DTT,0.005% Triton X-100). The final reaction volume was 25 μL and the finalconcentrations of recombinant CD73 and AMP were 0.5 nM and 50 μM,respectively. Reactions were allowed to proceed for 30 minutes at roomtemperature before the addition of 100 μL Malachite Green (CellSignaling Technology, Cat. No. 12776). After 5 minutes at roomtemperature, absorbance at 630 nm was determined on a microplatespectrophotometer. The concentration of inorganic phosphate wasdetermined using a phosphate standard curve. The IC₅₀ data is givenbelow in Table 3.

TABLE 3 Cpd. IC₅₀ # Compound (μM) 5

13.089 6

0.130 7

0.121 8

0.363 10

21.63 13

0.403 15

0.308 16

0.257 17

0.699 20

0.109 21

0.193 22

0.521 23

0.206 27

0.218 28

2.648 50

1.911 34

0.097 35

0.531 36

0.057 37

0.718 Isomer 1 38

0.686 Isomer 2 39

0.160 40

1.280 41

1.790 42

0.119 43

1.040 44

0.273 47

0.343 49

0.839 32

0.199 51

1.870 53

0.448 54

0.220 55

>50 56

0.168 57

0.142 58

0.038 59

0.439 60

0.051 61

2.246 63

1.222 64

0.860 65

0.031 66

0.133 67

0.602 68

0.322 73

8.614 74

1.659 75

0.887 76

0.074 77

0.255 78

0.086 79

0.029 80

0.044 81

2.857 Isomer 1 82

3.433 Isomer 2 83

6.443 84

7.261 Isomer 1 84

8.264 Isomer 2 85

0.183 86

0.062 87

0.083 88

0.238 89

0.043 91

0.322 92

0.172 94

0.906 95

0.105 96

0.788 97

3.432 98

0.512 107

42.47 108

0.104 109

0.601 110

0.066 111

0.141 113

0.161 114

1.567 115

0.238 116

0.146 117

63.9 118

>200 119

28.04 120

54.51 122

0.032 123

0.152 124

0.135 125

0.242 126

25.333 127

0.149 128

0.258 129

0.022 130

0.240 131

0.098 133

0.742 134

0.087 135

0.111 136

0.110 139

16.523 140

0.030 141

0.060 142

0.067 143

0.136 144

0.065 145

0.106 146

0.181 149

0.051 150

0.016 151

0.031 152

0.034 153

0.074 154

1.800 155

0.047 156

0.086 157

0.034 158

0.105 159

0.076 160

0.012 162

0.054 165

8.926 166

>10 167

>40 168

1.747 169

0.119 171

0.114 174

<0.020 175

0.018 176

0.056 177

0.048 178

0.016 179

0.009 180

>100 181

0.009 182

>50 188

11.525 mixture of diastereomers 189

0.227 mixture of diastereomers 190

0.300 mixture of diastereomers 191

0.130 192

1.178 mixture of diastereomers 193

>50 194

0.273 195

>50 197

2.433 198

0.029 199

0.118 200

0.053 201

0.386 202

>50 203

1.107 204

7.847

In Table 4, the IC₅₀ data is as follows: A is <1 μM, B is 1-3 μM, and Cis >3 μM.

TABLE 4 IC₅₀ Compound (μM)

A 14

A 100

C and

101 and 102

A and

103 and 104

Example 81 Biological Activity of Disclosed Compounds In Vitro

The ability of compounds to inhibit endogenous, cell-bound CD73 enzymeactivity was demonstrated using SK-MEL-28 cells, which express CD73 ontheir surface. The day before the experiment, 5000 cells were plated perwell in a 96-well plate. Cells were washed twice with 200 μL reactionbuffer (20 mM HEPES, pH 7.4, 125 mM NaCl, 1 mM KCl, 2 mM MgCl2, 10 mMglucose) to remove residual inorganic phosphate. After washing, assayscontained serial dilutions of test compounds and 100 μM of AMP in atotal volume of 200 μL reaction buffer, with a final DMSO concentration<0.5%. After 30 minutes at room temperature, supernatant was removedfrom the cells. A volume of 100 μL Malachite Green (Cell SignalingTechnology, Cat. No. 12776) was added to 25 μL of supernatant. After 5minutes at room temperature, absorbance at 630 nm was determined on amicroplate spectrophotometer. The concentration of inorganic phosphatewas determined using a phosphate standard curve to determine ICso. Table5 provides the IC₅₀ data of a representative number of compounds.

TABLE 5 Cpd. IC₅₀ # Compound (μM) 6

0.489 7

0.257 8

0.772 13

2.19 15

1.579 16

1.024 17

1.814 20

0.611 21

0.510 22

1.135 23

0.480 27

0.886 50

6.368 34

0.153 35

0.261 36

0.197 37

0.598 Isomer 1 38

1.485 Isomer 2 39

0.493 40

2.411 41

4.885 42

0.887 43

9.921 44

1.006 47

0.669 49

2.382 32

2.317 51

4.344 53

2.598 54

0.973 55

>50 56

1.250 57

0.1.250 58

0.853 59

6.984 60

0.512 61

6.974 63

2.006 64

0.588 65

0.196 66

0.426 67

1.309 68

0.924 73

1.243 74

2.557 75

0.990 76

0.305 77

1.331 78

0.234 79

0.162 80

0.177 81

2.109 Isomer 1 82

4.122 Isomer 2 83

5.196 85

1.368 86

0.626 87

0.549 88

0.443 89

0.070 92

0.202 108

0.246 109

1.912 110

0.361 111

0.182 113

0.161 114

1.567 115

0.872 116

0.267 122

0.147 123

0.387 124

0.636 125

0.836 127

0.408 128

0.827 129

0.086 130

1.045 131

0.285 133

>1 134

1.489 135

0.272 136

1.87 189

0.597 mixture of diastereomers 190

0.927 mixture of diastereomers 191

0.215 192

7.161 mixture of diastereomers 194

1.709 197

2.433 198

0.175 199

0.665 200

0.110 201

1.822 203

4.769

In Table 6, the IC₅₀ data is as follows: A is <1 μM, B is 1-3 μM, and Cis >3 μM. ND is not disclosed.

TABLE 6 IC₅₀ Compound (μM)

A 100

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

1. A compound of formula (I):

or a pharmaceutically acceptable salt and/or prodrug thereof, wherein Xis O, NR⁷ or CR⁷R⁸; Y is O or S; Z is NR¹⁹, O or S; Het is heterocyclylor heteroaryl; R^(1a) is selected from H, halo, hydroxy, cyano, azido,amino, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, amino-C₁₋₆alkyl,—O—C(O)—O—C₁₋₆alkyl, C₁₋₆acyloxy, C₁₋₆alkoxy, C₂₋₆alkenyl, andC₂₋₆alkynyl; and R^(1b) is selected from H, halo, C₁₋₆alkyl,hydroxy-C₁₋₆alkyl, amino-C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl; orR^(1a) and R^(1b), together with the carbon atom to which they areattached, form a C═CH₂ or C═C(H)C₁₋₆alkyl; R^(2a) is selected from H,halo, hydroxy, cyano, azido, amino, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,amino-C₁₋₆alkyl, C₁₋₆acyloxy, —O—C(O)—O—C₁₋₆alkyl, C₁₋₆alkoxy,C₂₋₆alkenyl, and C₂₋₆alkynyl; R^(2b) is selected from H, halo,C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, amino-C₁₋₆alkyl, C₂₋₆alkenyl, andC₂₋₆alkynyl; or R^(2a) and R^(2b), together with the carbon atom towhich they are attached, form a C═CH₂ or C═C(H)C₁₋₆alkyl; R³ is selectedfrom H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and—(CH₂)—C(O)OR₉; R⁴ is selected from heteroaryl, alkyl, —C(O)OR⁹,—C(O)NR¹¹R¹², —S(O)₂R¹⁰, —P(O)(OR¹¹)(OR¹²), and —P(O)(OR¹¹)(NR¹³R¹⁵); R⁵is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl,aralkyl, heteroaralkyl, and —C(O)OR⁹; R⁶ is selected from —C(O)OR⁹ and—P(O)(OR¹¹)(OR¹²); each R⁷ and R⁸ is H R⁹ is independently selected fromH, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, andheteroaralkyl, and —(CHR¹³)_(m)—Z—C(O)—R¹⁴; each R¹⁰ is independentlyselected from alkyl, alkenyl, alkynyl, amino, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, and heteroaralkyl; and each R¹¹ and R¹² is independentlyselected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and—(CHR¹³)_(m)—Z—C(O)—R¹⁴; or R¹¹ and R¹², together with the atoms towhich they are attached, form a 5- to 7-membered heterocyclyl; and eachR¹³ is independently H or alkyl; each R¹⁴ is independently selected fromalkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl; R¹⁵ is selectedfrom alkyl, aralkyl, —C(R¹⁶)(R¹⁷)—C(O)O—R¹⁸; each R¹⁶ and R¹⁷ areselected from H, alkyl, amino-alkyl, hydroxy-alkyl, mercapto-alkyl,sulfonyl-alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl,heteroaralkyl, and —(CH₂)C(O)OR⁹; R¹⁸ is selected from H, alkyl,alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl; R¹⁹ is H or alkyl, preferably H; and m is 1 or 2;provided that either R⁴ is tetrazolyl, or R⁵ is aralkyl orheteroaralkyl, or both.
 2. The compound of claim 1, wherein R^(1a) isselected from H, halo, hydroxy, cyano, azido, amino, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₆acyloxy, C₁₋₆alkoxy, C₂₋₆alkenyl,and C₂₋₆alkynyl.
 3. The compound of claim 1, wherein R^(1a) is fluoro.4. The compound of claim 1, wherein R^(1a) is chloro. 5-7. (canceled) 8.The compound of claim 1, wherein R^(1a) is hydroxy. 9-14. (canceled) 15.The compound of claim 1, wherein R^(2a) is selected from H, halo,hydroxy, cyano, azido, amino, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,amino-C₁₋₆alkyl, C₁₋₆acyloxy, C₁₋₆alkoxy, C₂₋₆alkenyl, and C₂₋₆alkynyl.16-19. (canceled)
 20. The compound of claim 1, wherein R^(2a) isC₁₋₆alkyl.
 21. The compound of claim 1, wherein R^(2a) is hydroxy.22-25. (canceled)
 26. The compound of claim 1, wherein R^(2a) isethynyl. 27-32. (canceled)
 33. The compound of claim 1, wherein R^(2b)is C₁₋₆alkyl.
 34. The compound of claim 1, wherein R^(1a) is fluoro andR^(1b) is H. 35-41. (canceled)
 42. The compound of claim 1, whereinR^(1a) is fluoro and R^(2a) is hydroxy.
 43. The compound of claim 1,wherein R^(1a) is chloro and R^(2a) is hydroxy. 44-48. (canceled) 49.The compound of claim 1, wherein R^(1a) is hydroxy and R^(2a) isC₁₋₆alkyl.
 50. (canceled)
 51. The compound of claim 1, wherein R^(1a) ishydroxy and R^(2a) is hydroxyl and R^(2b) is C₁₋₆alkynyl.
 52. Thecompound of claim 1, wherein R^(1a) is hydroxy and R^(2a) isC₁₋₆alkynyl. 53-67. (canceled)
 68. The compound of claim 1 wherein R³ isH.
 69. The compound of claim 1, wherein R³ is unsubstituted C₁₋₆alkyl.70. The compound of claim 1, wherein R³ is alkyl, and the alkyl isunsubstituted or substituted with one or more substituents selected fromhalo, CN, NO₂, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl,thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate,urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl,phosphoryl, phosphate, phosphonate, and phosphinate.
 71. The compound ofclaim 70, wherein the substituents are selected from halo, CN, azido,alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. 72-73. (canceled)74. The compound of claim 1, wherein R⁴ is heteroaryl.
 75. The compoundof claim 1, wherein R⁴ is tetrazolyl.
 76. The compound of claim 1,wherein R⁴ is selected from —C(O)OR₉, —C(O)NR₁₁R₁₂, —S(O)₂R₁₀, and—P(O)(OR₁₁)(OR₁₂).
 77. The compound of claim 1, wherein R⁴ is —C(O)OR₉.78. The compound of claim 1, wherein R⁴ is alkyl.
 79. The compound ofclaim 1, wherein R⁴ is —C(O)NR¹¹R¹².
 80. The compound of claim 1,wherein R⁵ is selected from alkyl, cycloalkylalkyl, heterocyclylalkyl,aralkyl and heteroaralkyl, and each is unsubstituted or substituted withone or more substituents, selected from halo, CN, NO₂, azido, hydroxy,alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino,amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido,sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate,phosphinate, cycloalkyl, heterocyclyl, arylalkyl and heteroarylalkyl.81. The compound of claim 80, wherein the substituents are selected fromhalo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. 82.The compound of claim 1, wherein R⁵ is selected from H, alkyl,cycloalkylalkyl, heterocyclylalkyl, aralkyl, and heteroaralkyl. 83.(canceled)
 84. The compound of claim 1, wherein R⁵ is H or aralkyl. 85.The compound of claim 1, wherein R⁵ is aralkyl or heteroaralkyl.
 86. Thecompound of claim 85, wherein R⁵ is heteroaralkyl, wherein theheteroaryl ring is selected from benzofuranyl, benzothienyl,benzothiazolyl, pyridyl, thienyl, furanyl, pyrazolyl, thiazolyl, andoxazolyl, and oxadiazolyl, each of which may be substituted orunsubstituted.
 87. The compound of claim 85, wherein R⁵ is unsubstitutedor substituted with one or more substituents selected from halo, CN, OH,alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy,aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl,alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl.
 88. Thecompound of claim 87, wherein the substituents are selected from halo,CN, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, and aryl.
 89. Thecompound of claim 87, wherein the substituents are selected fromtetrazolyl, substituted or unsubstituted phenyl, or substituted orunsubstituted benzyl. 90-92. (canceled)
 93. The compound of claim 87,wherein R⁵ is unsubstituted or substituted with one or moresubstituents, selected from chloro, trifluoromethyl, trifluoromethoxy,phenyloxy, dimethylamido, methylsulfonyl, CN, and carboxylic acid. 94.The compound of claim 1, wherein R⁶ is —C(O)OR₉.
 95. (canceled)
 96. Thecompound of claim 1, wherein R⁷ is H or C₁₋₆alkyl.
 97. The compound ofclaim 1, wherein R⁸ is H.
 98. The compound of claim 1, wherein R⁹ is H,C₁₋₆alkyl or amido.
 99. The compound of claim 1, wherein R⁹ is H, methylor ethyl.
 100. The compound of claim 1, wherein R¹¹ and R¹² are each H.101. The compound of claim 1, wherein R¹¹ and R¹² are each alkyl. 102.The compound of claim 1, wherein each R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² isindependently selected from alkyl, alkenyl, alkynyl, amido, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycylalkyl, aryl, aralkyl,heteroaryl, and heteroaralkyl, and each is unsubstituted or substituted,with one or more selected from halo, CN, NO₂, azido, hydroxy, alkoxy,alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino,amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido,sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, andphosphinate.
 103. The compound of claim 102, wherein the sub stituentson each R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are selected from halo, CN, azido,alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.
 104. The compound ofclaim 1, wherein X is O.
 105. The compound of claim 1, wherein Y is O.106-107. (canceled)
 108. The compound of claim 1, wherein Z is O. 109.The compound of claim 1, wherein Het is a nitrogen-containingheterocyclyl or heteroaryl. 110-111. (canceled)
 112. The compound ofclaim 1, wherein Het is a 5- to 8-membered monocyclic or 5- to10-membered bicyclic heteroaryl and is unsubstituted or substituted,with one or more substituents selected from halo, CN, NO₂, azido,hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino,imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido,sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate,phosphonate, and phosphinate.
 113. The compound of claim 112, whereinthe substituents are selected from halo, CN, azido, alkoxy, carbonyl,amino, amido, and alkoxycarbonyl. 114-115. (canceled)
 116. The compoundof claim 1, wherein Het is


117. The compound of claim 1, wherein Het is selected from


118. The compound of claim 1, wherein Het is substituted with one or twosubstituents selected from halo, aralkyl, amino, azido and hydroxy. 119.The compound of claim 118, wherein Het is selected from


120. The compound of claim 1, wherein


121. The compound of claim 1, wherein


122. The compound of claim 1, wherein

where each R_(A) is independently selected from H, halo, CN, OH, alkyl,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl,alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl; and k is1, 2, or
 3. 123. The compound of claim 122, wherein R_(A) is selectedfrom pyridyl, pyrazolyl, pyrrolidinonyl, azapanonyl, morpholinonyl,piperazonyl, tetrahydropyrimidinonyl, phenyl, and benzyloxy. 124-146.(canceled)
 147. A compound selected from: Cpd. # Compound Name 6

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-benzylmalonic acid 7

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-(4-carboxybenzyl)- malonic acid 8

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-((6-chloropyridin-3- yl)methyl)malonic acid 10

2-(((2R,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-benzylmalonicacid 12

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-carboxyethyl)benzyl)malonic acid 13

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-phenoxybenzyl)malonic acid 15

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethoxy)benzyl)malonic acid 16

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(trifluoromethyl)benzyl)malonic acid 17

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (naphthalen-2-ylmethyl)malonicacid 20

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethyl)benzyl)malonic acid 21

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methylsulfonyl)benzyl)malonic acid 22

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-(dimethylcarbamoyl)benzyl)malonic acid 23

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (thiophen-3-ylmethyl)malonicacid 25

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- (isobutyryloxy)tetrahydrofuran-2-yl)methoxy)-2-(4- (trifluoromethoxy)benzyl)malonate 27

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-aminobenzyl)malonic acid 28

2-benzyl-2-(((2R,3R,4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)malonic acid 32

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- ((6-(trifluoromethyl)pyridin-3-yl)methyl)malonic acid 34

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-cyanobenzyl)malonic acid 35

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-cyanobenzyl)malonic acid 36

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethoxy)benzyl)malonic acid 37

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3- ethoxy-3-oxo-2-(4-(trifluoromethoxy)benzyl)propanoic acid Isomer 1 38

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3- ethoxy-3-oxo-2-(4-(trifluoromethoxy)benzyl)propanoic acid Isomer 2 39

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(hydroxymethyl)benzyl)malonicacid 40

2-(((2R,3R,4S,5R)-5-(6-amino-2-azido-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-cyanobenzyl)malonic acid 41

2-(((2R,3R,4S,5R)-5-(2-azido-6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3-cyanobenzyl)malonicacid 42

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2- (3-carboxybenzyl)-malonic acid43

2-(3-(1H-tetrazol-5-yl)benzyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-azido-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonicacid 44

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-fluorobenzyl)malonic acid 45

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-fluorobenzyl)malonate 46

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-fluorobenzyl)malonate 47

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-fluorobenzyl)malonic acid 48

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethoxy)benzyl)malonate 49

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-methoxybenzyl)malonic acid 50

2-((1H-tetrazol-5-yl)methyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonicacid 51

2-(((2S,3S,4R,5R)-3-amino-5-(6-amino-2- chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-2- benzylmalonic acid 53

2-(3-(1H-tetrazol-5-yl)benzyl)-2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)malonic acid 54

2-(4-(1H-tetrazol-5-yl)benzyl)-2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)malonicacid 55

2-(((2R,3S,4R,5R)-4-amino-5-(6-amino-2- chloro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- benzylmalonic acid 56

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-hydroxybenzyl)malonic acid 57

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxy-2-fluorobenzyl)malonic acid 58

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-(4-carboxy-3-fluorobenzyl)malonic acid 59

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2- ((5-(trifluoromethyl)-furan-2-yl)methyl)malonic acid 60

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-(3-fluoro-4-(trifluoromethyl)benzyl)malonic acid 61

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((3-phenylisoxazol-5-yl)methyl)malonic acid 62

dimethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(trifluoromethyl)benzyl)malonate 63

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-((1-benzyl-1H-pyrazol-4-yl)methyl)malonic acid 64

2-((1H-pyrazol-4-yl)methyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonicacid 65

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(benzyloxy)benzyl)malonicacid 66

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-hydroxybenzyl)malonic acid 67

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-((2-carboxythiazol-5-yl)methyl)malonic acid 68

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-((2-carboxythiazol-4-yl)methyl)malonic acid 69

2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-3-ethoxy-3- oxopropanoic acid Isomer 1 70

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-methoxy-2-oxoethyl)benzyl)malonate 71

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3- (isobutyryloxy)tetrahydrofuran-2-yl)methoxy)-2-((5- (methoxycarbonyl)thiophen-3- yl)methyl)malonate 72

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((5-(methoxycarbonyl)-1-methyl-1H- pyrazol-3-yl)methyl)malonate 73

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((5-carboxy-1-methyl-1H-pyrazol-3- yl)methyl)malonic acid 74

2-benzyl-2-(((2R,3R,4S,5R)-5-(2-chloro-6-hydroxy-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)malonic acid 75

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-cyano-3-fluorobenzyl)malonicacid 76

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-((5-carboxythiophen-3-yl)methyl)malonic acid 77

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-((5-carboxythiophen-2-yl)methyl)malonic acid 78

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(carboxymethyl)benzyl)malonicacid 79

2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)malonicacid 80

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-chloro-2-fluorobenzyl)malonicacid 81

2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3- methoxy-3-oxopropanoic acidIsomer 1 82

2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-3- methoxy)-3-oxopropanoic acidIsomer 2 83

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((3-carboxyisoxazol-5-yl)methyl)malonic acid 84

2-([1,1′-biphenyl]-4-ylmethyl)-2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-3-ethoxy-3- oxopropanoic acid Isomer 2 85

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(3-chloro-4-methoxybenzyl)malonic acid 86

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-sulfamoylbenzyl)malonic acid87

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2- (4-((2-carboxy-ethyl)carbamoyl)benzyl)malonic acid 88

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydro-furan-2-yl)methoxy)-2-((2-carboxybenzofuran-5-yl)methyl)malonic acid 89

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2,2,2-trifluoroethoxy)benzyl)malonic acid 90

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-((E)-2-carboxyvinyl)benzyl)malonic acid 91

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methoxycarbonyl)benzyl)malonic acid 92

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(carboxymethoxy)benzyl)malonic acid 93

2-benzyl-2-(((2R,3R,4S,5R)-5-(2-chloro-6-oxo-1H-purin-9(6H)-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)malonic acid 94

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)malonic acid 95

of 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((2′-cyano-[1,1′-biphenyl]-4-yl)- methyl)malonic acid 96

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-((5-chlorobenzo[b]thiophen-3-yl)methyl)- malonic acid 97

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(benzo[d]thiazol-2-ylmethyl)malonic acid 98

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(methylcarbamoyl)benzyl)malonic acid 99

Diethyl 2-(((2R,3S,4R,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2- benzyl malonate 100

2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(4-carboxybenzyl)malonic acid 101

S)-2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2- (1H-tetrazol-5-yl)acetic acid102

(R)-2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2- (1H-tetrazol-5-yl)acetic acid103

(S)-2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoic acid 104

(R)-2-(((2R,3S,4R,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoic acid 105

(S)-2-(((2R,3S,4R,5R)-5-(6-amino-2- methoxy-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoic acid 106

(R)-2-(((2R,3S,4R,5R)-5-(6-amino-2- methoxy-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-phenyl-2-(1H-tetrazol-5-yl)propanoic acid

Cpd. # Compound 108

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or a pharmaceutically acceptable salt thereof.
 148. A compound selectedfrom:

or a pharmaceutically acceptable salt thereof.
 149. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.
 150. A method of inhibiting CD73in a cell, comprising contacting the cell with a compound of formula(I), or a pharmaceutically acceptable salt thereof, according toclaim
 1. 151. The method of claim 150, wherein contacting the celloccurs in a subject in need thereof, thereby treating a disease ordisorder selected from cancer, cerebral and cardiac ischemic diseases,fibrosis, immune and inflammatory disorders, inflammatory gut motilitydisorder, neurological, neurodegenerative and CNS disorders anddiseases, depression, Parkinson's disease, and sleep disorders. 152-158.(canceled)